Genetic markers of mental illness

ABSTRACT

This invention relates to genetic markers of mental illness, e.g., schizophrenia (SZ), and methods of use thereof.

CLAIM OF PRIORITY

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/021,756, filed on Jan. 17, 2008, the entirecontents of which are hereby incorporated by reference.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant Nos. R43MH078437, N01 MH900001, and MH074027, awarded by the National Institutesof Health. The Government has certain rights in the invention.

ACKNOWLEDGEMENT

This invention was made with an award from the Kentucky Cabinet forEconomic Development, Department of Commercialization and Innovation,under Grant Agreement KSTC-184-512-07-007 with the Kentucky Science andTechnology Corporation.

TECHNICAL FIELD

This invention relates to genetic markers of mental illness, e.g.,schizophrenia (SZ), and methods of use thereof, e.g., for determining asubject's risk of developing a mental illness, e.g., SZ.

BACKGROUND

Schizophrenia (SZ) is a severe and persistent debilitating psychiatricillness that is generally associated with considerable morbidity andextreme disability. Due to the severity of this disorder, especially thenegative impact of a psychotic episode on a patient, and the diminishingrecovery after each psychotic episode, there is a need to moreconclusively identify individuals who have or are at risk of developingSZ, for example, to confirm clinical diagnoses, to allow forprophylactic therapies, to determine appropriate therapies based ontheir genotypic subtype, and to provide genetic counseling forprospective parents with a history of the disorder.

Various genes and chromosomes have been implicated in etiology of SZ.Whole genome scans for genes involved in SZ and related SZ-spectrumdisorders (including schizotypal personality disorder (SPD) andschizoaffective disorder (SD)) have implicated numerous autosomes ashaving a role in the genetic etiology of SZ and related SZ-spectrumdisorders (Badner et al., Mol. Psychiatry 7:405-411 (2002) Bennett etal., Mol. Psychiatry 7:189-200 (2002) Cooper-Casey et al., Mol.Psychiatry 10:651-656 (2005) Devlin et al., Mol. Psychiatry 7:689-694(2002) Fallin et al., Am. J. Hum. Genet. 73:601-611 (2003) Ginns et al.,Proc. Natl. Acad. Sci. U.S.A 95:15531-15536 (1998) Jablensky, Mol.Psychiatry (2006) Kirov et al., J. Clin. Invest 115:1440-1448 (2005)Norton et al., Curr. Opin. Psychiatry 19:158-164 (2006) Owen et al.,Mol. Psychiatry 9:14-27 (2004)). Generally, these linkage scans have aretoo low in resolution to identify specific genes, but increasingly,transmission disequilibrium (TDT, family-based association) andCase/Control association studies have evaluated a number of positionalcandidate genes with a good measure of success (Fallin et al., Am. J.Hum. Genet. 77:918-936 (2005)).

SUMMARY

The invention includes methods for assessing genetic risk, aiding indiagnosis, and/or stratifying patient populations in order to selectoptimal treatments based on evaluation of single nucleotidepolymorphisms (SNPs) for a number of bioinformatically identified geneson chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and 20relating to SZ (which herein is broadly defined to include SZ-spectrumdisorders, e.g., including schizophrenia (SZ), schizotypal personalitydisorder (SPD) and schizoaffective disorder (SD)). Exemplary SNPsdelimiting each gene region (referred to herein as “delimiting SNPs”)are given along with exemplary test SNPs that can be used to capturesignificant haplotype variation in these genes. Important variants canbe identified via TDT using families with multiple affected individuals(such as those collected CCGS) and verified by Case/Control comparisonsusing the SNP markers presented herein. Using SNP markers lying betweenthe delimiting SNPs, inclusive, and identical to or in linkagedisequilibrium with the exemplary SNPs, one can determine the haplotypesin these genes relating to genetic risk of developing SZ. Thesehaplotypes can then be used to determine risk of developing SZ byCase/Control studies as shown in Example 1. The allelic and genotypicvariants thus identified can be used for assessing genetic risk, to aidin diagnosis, and/or to stratify patient population in order to selectoptimal treatments (atypical antipsychotic, typical antipsychotic,and/or psychosocial intervention) for patients.

Numerous pathways have been implicated in SZ etiology. As describedherein, genes identified as associated with increased risk of SZ areinvolved in a number of pathways including: glutamate signaling andmetabolism, cell adhesion, cytoskeletal architecture, vesicle formationand trafficking, G-protein coupled receptors, carrier proteins andtransporters, ion channels (e.g., potassium channels), and potassiumcurrent signaling molecules, cell cycle modulators, neuronaldevelopment, calcium/calmodulin signaling, neuropeptide signaling,inositol signaling (e.g., phosphatidylinositol kinases), insulinsignaling, diacylglycerol signaling, and several additional genesidentified by virtue of their interaction with genes in high impactpathways and their expression in the central nervous system.

Table A lists gene names and delimiting SNPs for bioinformaticallyidentified genes relating to SZ-spectrum disorders. All of the genes arehuman.

TABLE A Delimiting SNPs for Novel SZ Genes (NCBI Genome Build 36.2) GeneChrom. SNP 1 Location (bp) SNP 2 Location (bp) Delimiting SNPs forPotassium Channel and Related Genes KCNC4 1 rs1359149 110,553,057rs11578913 110,578,628 KCNA10 1 rs1281177 110,859,992 rs17025957110,863,572 KCND3 1 rs197422 112,119,035 rs10745323 112,345,127 KCNH1 1rs12126648 208,922,743 rs1538287 209,377,867 ANK3 10 rs105074561,457,255 rs1551684 61,820,209 KCNQ1 11 rs11022827 2,414,908 rs22398972,848,541 KCNC1 11 rs7949069 17,711,203 rs1236205 17,760,287 DelimitingSNPs for Cell Adhesion and Related Genes RP1-21O18.1 1 rs966301015,143,609 rs2235789 15,314,645 CTNND1 11 rs558653 57,285,706 rs65290857,360,585 DACT1 14 rs464582 58,171,201 rs160472 58,185,201 CDH11 16rs35148 63,536,690 rs7204464 63,731,895 Delimiting SNPs forVesicle-Related Genes VAMP4 1 rs10913508 169,935,102 rs7556644169,979,491 SYT14 1 rs9429830 208,177,160 rs11119426 208,407,592 BRSK211 rs7395835 1,365,307 rs1554857 1,441,643 SYT13 11 rs2863172 45,217,918rs11038382 45,269,392 STX2 12 rs2632601 129,834,650 rs7962097129,890,817 RTN1 14 rs17255975 59,131,314 rs7144589 59,407,620 UNC13C 15rs11071015 52,092,152 rs9920150 52,708,142 SV2B 15 rs11630131 89,569,404rs7169918 89,640,060 Delimiting SNPs for Genes Related to GlutamatePathways Gcom1 15 rs1908202 55,669,589 rs1808478 55,797,051 GRINL1A 15rs1908202 55,669,589 rs1808478 55,797,051 GOT2 16 rs2042445 57,296,647rs4238801 57,329,680 Delimiting SNPs for G-Protein Coupled ReceptorRelated Genes RHOG 11 rs1055640 3,803,869 rs4406820 3,819,109 GPR135 14rs17255731 58,964,865 rs4898989 59,005,097 AKAP13 15 rs153312483,674,688 rs11637212 84,094,101 Delimiting SNPs for Hormone, Inositol,and Diacylglyceride Related Genes HSD17B12 11 rs12364003 43,657,684rs11037691 43,848,213 IGF1R 15 rs35554027 97,008,574 rs702497 97,319,104Delimiting SNPs for Cytoskeletal, Myosin, Actin and Microtubule RelatedGenes EVL 14 rs1190954 99,601,206 rs35257667 99,689,766 KATNAL2 18rs9304340 42,780,580 rs1434528 42,886,321 Delimiting SNPs for Genes forCarrier Proteins and Transporters SLC6A17 1 rs924181 110,481,637rs545849 110,546,538 SLC16A4 1 rs10857820 110,706,448 rs12127781110,738,080 SLC6A5 11 rs894747 20,575,165 rs1401793 20,632,993 SLC17A611 rs1155821 22,315,296 rs2593644 22,357,697 SLCO3A1 15 rs1185812090,196,267 rs1060206 90,509,554 Delimiting SNPs for Cell Cycle and TumorSuppressor/Promoter Related Genes RERE 1 rs1055236 8,326,680 rs9149948,839,799 FASLG 1 rs763110 170,894,121 rs12135884 170,905,123 DEAF1 11rs936465 633,568 rs6597990 687,761 HCCA2 11 rs12786504 1,446,780rs2334652 1,462,030 PTPN5 11 rs873670 18,705,395 rs7932938 18,771,871CHFR 12 rs1531822 131,925,194 rs3741494 131,974,573 TTC5 14 rs1013094219,826,245 rs10873395 19,845,685 FUSSEL18 18 rs2137289 43,006,123rs892583 43,170,372 SMAD2 18 rs1792666 43,617,212 rs2000709 43,713,512SMAD7 18 rs9944944 44,699,493 rs736839 44,782,063 SMAD4 18 rs62089846,763,146 rs12456284 46,863,966 Delimiting SNPs for Genes Involved inNeuronal Development and Plasticity DNM3 1 rs6701033 170,076,599 rs13932170,678,391 TOLLIP 11 rs5744038 1,252,012 rs5743854 1,287,830 DUSP8 11rs6578504 1,532,811 rs10734456 1,563,922 NAV2 11 rs890136 19,687,211rs2246192 20,098,415 LRRC4C 11 rs11035693 40,091,818 rs1012863940,275,738 RTN4RL2 11 rs2729363 56,983,430 rs2955849 57,005,697 DTX4 11rs10896947 58,694,659 rs544864 58,735,516 ULK1 12 rs11246867 130,943,970rs7978708 130,977,857 NDRG2 14 rs1263871 20,553,926 rs1243451 20,564,197JPH4 14 rs12897422 23,102,867 rs222732 23,129,120 DAAM1 14 rs1709596558,718,491 rs4127823 58,926,458 NEDD4 15 rs4424863 53,905,753 rs150940854,073,605 RGMA 15 rs12438714 91,386,979 rs4114 91,443,429 N4BP1 16rs9937623 47,129,091 rs9936446 47,203,308 NDRG4 16 rs7202037 57,054,471rs2280397 57,109,729 CDH8 16 rs4131634 60,243,900 rs9302540 60,629,024BEAN 16 rs6499082 64,992,072 rs12445633 65,114,761 KIAA0513 16 rs187524683,617,069 rs1466864 83,691,111 DYM 18 rs288812 44,821,479 rs1772548145,241,155 DCC 18 rs7753970 48,119,269 rs2270954 49,311,296 BMP7 20rs6014947 55,177,906 rs2208404 55,277,143 TMEPAI 20 rs6025689 55,656,857rs6015068 55,734,303 Delimiting SNPs for Calcium/Calmodulin RelatedGenes CAMTA1 1 rs449250 6,720,271 rs228651 7,833,686 CACNA1E 1 rs541886179,718,012 rs635118 180,037,358 CAMK1G 1 rs17014820 207,823,042rs926387 207,854,836 RIMBP2 12 rs1496858 129,444,850 rs7963990129,571,289 Delimiting SNPs for Genes Involved in Hereditary HearingLoss DPH3 3 rs2292614 16,276,795 rs2245708 16,281,022 EXOC2 6 rs10900954428,817 rs13205146 638,473 USH1C 11 rs4756895 17,470,828 rs207358217,523,687 OTOG 11 rs2073582 17,523,687 rs11024358 17,624,137 SERGEF 11rs1236205 17,760,287 rs1133758 17,998,369 EML1 14 rs10140193 99,328,197rs7149272 99,487,743 PMP22 17 rs230938 15,071,845 rs179521 15,113,946Delimiting SNPs for Genes Encoding Zn-Finger Proteins PRDM2 1 rs248765713,894,681 rs979932 13,987,558 ZFP91-CNTF 11 rs1944055 58,099,205rs4319530 58,156,405 ZNF423 16 rs193907 48,080,956 rs12443775 48,418,620Delimiting SNPs for Brain-expressed Genes (not otherwise specified) PER31 rs172933 7,767,267 rs707472 7,828,595 RABGAP1L 1 rs6681627 172,393,365rs12126129 173,194,998 PHACS 11 rs178512 44,043,887 rs2285029 44,062,444YPEL4 11 rs1798177 57,168,726 rs1647394 57,175,164 KIAA1853 12 rs7979864117,902,236 rs722307 118,094,760 KIAA1545 12 rs10870551 131,567,365rs7294615 131,678,218 TEP1 14 rs1713418 19,904,649 rs1760890 19,951,629WDR25 14 rs2273802 99,912,652 rs10151709 100,067,090 BEGAIN 14rs11628965 100,071,902 rs7140556 100,106,211 HERC2 15 rs749517426,017,833 rs1614575 26,236,593 ADAM10 15 rs3764196 56,674,302 rs51404956,829,655 KLHL25 15 rs11637212 84,094,101 rs7181017 84,145,916 NETO2 16rs1551188 45,616,796 rs7184206 45,736,527 CBLN1 16 rs3743777 47,869,517rs9935379 47,884,582 KIAA0182 16 rs4240810 84,182,628 rs381579584,269,606 C16orf74 16 rs11644122 84,298,251 rs301143 84,342,400 COX1017 rs4792434 13,912,946 rs7218697 14,074,153 KIAA0427 18 rs103998944,318,592 rs752151 44,697,296

In one aspect, the invention includes methods for obtaining informationregarding a subject's risk for developing SZ, i.e., determining thesubject's risk of developing SZ. The methods include obtaining a testhaplotype associated with schizophrenia as described herein. The methodscan also include obtaining a sample comprising genomic DNA (gDNA) fromthe subject, and determining the identity, absence or presence of a testhaplotype associated with SZ as described herein. In some embodiments,the methods include obtaining a test haplotype for the subjectcomprising at least one test SNP marker that is found within the regiondelimited by SNP1 and SNP2, inclusive, for a given gene as specified inTable A, or comprising one or more of the exemplary SNP markers for eachgene, as specified in the Examples and/or SNP markers in linkagedisequilibrium with these markers, wherein the haplotype providesinformation regarding the subject's risk of developing SZ, SD, or SPD.In some embodiments, the test marker is a marker listed in one or moregenes of Table A that is in linkage disequilibrium (defined bycorrelation, [r²]≧0.5) with a marker listed in Table A in Table B asshown in the Examples, wherein the haplotype provides informationregarding the subject's risk of developing SZ, e.g., markers lyingbetween the exemplary SNPs for a gene listed in Table A, but notexplicitly listed in the Examples.

In some embodiments, the test haplotype includes at least one markerlying between delimiting SNPs (SNP1 and SNP2), inclusive, for a givengene as specified in Table A, e.g., the exemplary delimiting SNPs listedin Table A; other delimiting SNPs can be chosen from other SNPs known inthe art, e.g., the exemplary test SNPs described herein. In someembodiments, the test haplotype includes two or more markers from onegene. In some embodiments, the test genotype includes at least twomarkers, each from a different gene listed in Table A.

In some embodiments, the test haplotype includes at least one markerlying between the SNP1 and SNP2, inclusive, for a given gene asspecified in Table A and provides information regarding a subject's riskof developing SZ under a narrower (DSM III/DSM IV) disease definition.

In some embodiments, the methods include obtaining a test haplotype forthe subject by determining the genotype of at least one test markerlisted in Table B, or a test marker that lies between the delimitingmarkers listed in Table A and that is in linkage disequilibrium (LD,defined by correlation, [r²]≧0.5) with markers listed in Table B,wherein the test haplotype indicates the subject's risk of developingSZ. In some embodiments, the at least one test marker is in the KIAA0182gene or the KIAA0427 gene. In some embodiments, the test marker isselected from the group consisting rs736845; rs994060; rs381579;rs217556; rs8095199; or is a test marker in LD with these markers.

In some embodiments, the methods described herein can be used forpredicting a human subject's likely response to an antipsychoticmedication. The methods include obtaining a test haplotype for thesubject by determining the genotype for at least one test marker listedin Table B, or at least one test marker that lies between the delimitingmarkers in Table A and that is in linkage disequilibrium (LD) (definedby correlation, [r2]≧0.5) with a marker listed in Table B, wherein thetest haplotype indicates the subject's likely response, e.g., likelihoodof responding positively (i.e., an improvement in one or more symptomsof the disease) or negatively (i.e., with no improvement, or even aworsening, of one or more symptoms of the disease, or with excessiveside effects) to an antipsychotic medication. A number of antipsychoticmedications are known in the art and can include, for example,olanzapine, risperidone, quetiapine, perphenazine, and ziprasidone.

In some embodiments, the treatment is administration of olanzapine, andthe at least one test marker is in a gene selected from the groupconsisting of C16orf74, synaptic vesicle glycoprotein 2B (SV2B),calmodulin binding transcription activator 1 (CAMTA1), otogelin (OTOG),ras homolog gene family, member G (RHOG). In some embodiments, the testmarker is selected from the group consisting of rs230535; rs373835;rs386061; rs449250; rs657739; rs657740; rs755475; rs755475; rs141798;rs110300; rs145172; rs100349; rs108328; rs202348; rs110243; rs11024358;or is a test markers in LD with one of these markers, and the testhaplotype indicates the subject's likely response to administration ofolanzapine.

In some embodiments, the treatment is administration of risperidone, andthe at least one test marker is in a gene selected from the groupconsisting of neural precursor cell expressed, developmentallydown-regulated 4 (NEDD4), cadherin 8, type 2 (CDH8), deformed epidermalautoregulatory factor 1 (DEAF1), hect domain and RLD 2 (HERC2). In someembodiments, the test marker is selected from the group consisting ofrs230357; rs230358; rs139713; rs805733; rs930254; rs110754; rs136991;rs197879; rs649880; rs993999; rs496314; rs659799; rs936465; rs659799;rs110743; rs163516; rs223828; rs7495174; or is a test marker that is inlinkage disequilibrium with one of these markers. The test haplotypeindicates the subject's likely response to administration ofrisperidone.

In some embodiments, the treatment is administration of quetiapine, andthe at least one test marker is in a gene selected from the groupconsisting of catenin (cadherin-associated protein), delta 1 (CTNND1),reticulon 1 (RTN1), A kinase (PRKA) anchor protein 13 (AKAP13),potassium voltage-gated channel, shaker-related subfamily, member 10(KCNA10), solute carrier family 17 (sodium-dependent inorganic phosphatecotransporter), member 6 (SLC17A6). In some embodiments, the test markerfurther is selected from the group consisting of: rs207835; rs110265;rs115582; rs207835; rs224671; rs376845; rs708228; rs108966; rs115701;rs215663; rs652908; rs105399; rs206182; rs206182; rs206182; rs338523;rs407525; rs407525; rs484289; rs484307; rs484307; rs716216; rs110735;rs101450; rs127174; rs17310036; or is a test marker that is in linkagedisequilibrium with one of these markers. The test haplotype indicatesthe subject's likely response to administration of quetiapine.

In some embodiments, the treatment is administration of perphenazine,and the at least one test marker is in a gene selected from the groupconsisting of secretion regulating guanine nucleotide exchange factor(SERGEF) potassium voltage-gated channel, subfamily H (eag-related),member 1 (KCNH1), functional smad suppressing element 18 (FUSSEL18). Insome embodiments, the test marker is selected from the group consistingof: rs177022; rs139302; rs1528; rs172424; rs211130; rs211137; rs211146;rs228323; rs105028; rs177854; rs266877; rs723610; rs892583; or is a testmarker that is in linkage disequilibrium with one of these markers. Thetest haplotype indicates the subject's likely response to perphenazine.

In some embodiments, the treatment is administration of ziprasidone, andthe at least one test marker is in a gene selected from the groupconsisting of unc-13 homolog C (C. elegans) (UNC13C), cerebellin 1precurso (CBLN1), checkpoint with forkhead and ring finger domains(CHFR). In some embodiments, the test marker is selected from the groupconsisting of: rs129109; rs110764; rs993537; rs125945; rs116390;rs802519; rs930218; rs230653; rs4758954; or is a test marker that is inlinkage disequilibrium with one of these markers. The test haplotypeindicates the subject's likely response to administration ofziprasidone.

In some embodiments, the treatment is administration of an antipsychoticdrug, and the at least one test marker is in a gene selected from thegroup consisting of cadherin 11, type 2, OB-cadherin (osteoblast)(CDH11), deleted in colorectal carcinoma (DCC), Usher syndrome 1C(autosomal recessive, severe) (USH1C). In some embodiments, the testmarker is selected from the group consisting of: rs35144; rs35148;rs35186; rs35195; rs35144; rs222908; rs950278; rs143174; rs124574;rs494025; rs750690; rs650823; rs139333; rs152023; rs105557; rs105557;rs207222; rs475689; rs16770, or is a test marker that is in linkagedisequilibrium with one of these markers. The test haplotype indicatesthe subject's likely response to administration of an antipsychotic.

In some embodiments, the test haplotype provides information regarding asubject's risk (or likelihood) of having a particular endophenotype,and/or a higher or lower level (e.g., severity) of the endophenotype,e.g., of one or more specific parameters of the PANSS scale, e.g., oneor more symptoms, e.g., hallucinations, paranoia, anxiety, depression,or grandiosity, as well as response or lack of response to drugs andcomorbidity for substance and alcohol abuse.

In another aspect, the invention provides methods for predicting thedegree of severity of a psychiatric endophenotype in a human subject.The methods include obtaining a test haplotype for the subject bydetermining the genotype for at least one test marker listed in Table B,or at least one test markers that lies between the delimiting markerslisted in Table A and that is in linkage disequilibrium (LD) defined bycorrelation, [r²]≧0.5) with a marker in Table B, wherein the testhaplotype indicates the likely degree of severity of a psychiatricendophenotype in the subject. In some embodiments, the psychiatricendophenotype is a quantitative trait that can be measured using one ormore of PANSS Total composite score, PANSS Positive composite score,PANSS Negative composite score, and PANSS General Psychopathologycomposite score.

In some embodiments, the one or more test markers are from calciumchannel, voltage-dependent, R type, alpha 1E subunit (CACNA1E),echinoderm microtubule associated protein like 1 (EML1), katanin p60subunit A-like 2 (KATNAL2) genes. In some embodiments, the test markeris selected from the group consisting of rs174946; rs199960; rs385609;rs465267; rs704326; rs218709; rs224722; rs257103; rs257604; rs723351;rs930434; rs996138; rs225071; rs111605; rs111605; rs124336; rs657575;rs746698; rs227370; rs2273704; or is a test marker in linkagedisequilibrium with one of these markers. The test haplotype indicatesthe likely degree of severity of a psychiatric endophenotype in thesubject.

In some embodiments, the psychiatric endophenotype comprises one or moreof: a Positive Symptom selected from the group consisting ofP1-delusions, P2-conceptual disorganization, P3-hallucinatory behavior,P4-exitement, P5-grandiosity, P6-suspiciousness, P7-hostility; aNegative Symptom selected from the group consisting of N1-bluntedaffect, N2-emotional withdrawal, N3-poor rapport, N4-passive/appatheticsocial withdrawal, N5-difficulty in abstract thinking, N60 lack ofspontaneity and flow of conversation, N7-stereotyped thinking; or ageneral psychopathology symptom selected from the group consisting ofG1-somatic concern, G2-anxiety, G3-guilt feelings, G4-tension,G5-mannerisms and posturing, G6-depression, G7-motor retardation,G8-uncooperativeness, G9-unusual thought content, G10-disorientation,G11-poor attention, G12-lack of judgment and insight, G13 disturbance ofvolition, G14-poor impulse control, G15-preoccupation, and G16-activesocial avoidance.

In some embodiments, the at least one test marker is from a geneselected from the group consisting of DPH3, KTI11 homolog (DPH3),insulin-like growth factor I receptor (IGF1R),calcium/calmodulin-dependent protein kinase IG (CAMK1G), neuronnavigator 2 (NAV2), bone morphogenetic protein 7 (BMP7). In someembodiments, the test marker is selected from the group consisting ofrs224572; rs842257; rs859703; rs224570; rs496543; rs112473; rs187961;rs268479; rs108332; rs712564; rs10375; rs601494; rs230198; or is a testmarker that is in linkage disequilibrium with one of these markers. Thetest haplotype indicates the likely severity of a psychiatricendophenotype in the subject.

The methods described herein can include obtaining a haplotype thatincludes two or more, e.g., two, three, four, five, or six markers.

Additionally, the methods can include determining the presence orabsence of other markers known to be associated with SZ, SD, or SPD,e.g., outside of a region identified herein. A number of other suchmarkers are known in the art, e.g., as described herein.

The subject can be a human (e.g., a patient having, or at risk of, SZ).In one embodiment, the subject is a patient having previously diagnosedSZ, SD, or SPD (e.g., a patient suffering from early, intermediate oraggressive SZ, SD, or SPD). In some embodiments, the methods describedherein are used to obtain information regarding a subject's risk ofdeveloping SZ wherein the disorder is other than catatonicschizophrenia. In some embodiments, the subject is of Caucasian (CA)descent, i.e., has one or more ancestors who are CA.

In one embodiment, a subject to be evaluated by a method describedherein is a subject having one or more risk factors associated with SZ,SD, or SPD. For example, the subject may have a relative afflicted withSZ, e.g., one or more of a grandparent, parent, uncle or aunt, sibling,or child who has or had SZ, SD, or SPD; the subject may have agenetically based phenotypic trait associated with risk for SZ, SD, orSPD (e.g., eye tracking dysfunction); deficits in working (short-term)memory; and/or mixed-handedness (the use of different hands fordifferent tasks), particularly in females.

In some embodiments, the subject is a child, fetus, or embryo, and oneof the subject's relatives, e.g., a parent or sibling, of the child,fetus, or embryo has SZ, SD, or SPD. In this case, the presence in thechild, fetus, or embryo of a haplotype described herein that is sharedwith the affected parent, but not with the non-affected parent,indicates that the child, fetus, or embryo has an increased risk ofdeveloping SZ. In some embodiments, the subject has no overt or clinicalsigns of SZ, SD, or SPD.

In some embodiments, obtaining a test haplotype includes obtaining asample comprising DNA from the subject; and determining the identity,presence or absence of at least one test marker that is SNP marker thatis found within the region delimited by SNP1 and SNP2, inclusive, for agiven as specified in Table A, or comprising one or more of theexemplary SNP markers for each gene, as specified in the Table B and/orSNP markers in linkage disequilibrium with these markers (in theparticular population) in the DNA. The sample can be obtained, e.g.,from the subject by a health care provider, or provided by the subjectwithout the assistance of a health care provider.

In some embodiments, obtaining a test haplotype includes reviewing asubject's medical history, wherein the medical history includesinformation regarding the presence or absence of at least one test SNPmarker that is found within the region delimited by SNP1 and SNP2,inclusive, for a given gene as specified in Table A, or comprising oneor more of the exemplary SNP markers for each gene, as specified inTable B, and/or SNP markers in linkage disequilibrium with thesemarkers, in the subject.

In some embodiments, the methods described herein include obtaining areference haplotype including a reference marker that corresponds to atest marker, and comparing the test haplotype to the referencehaplotype. A reference marker that “corresponds to” a test marker is thesame marker. For example, if the test haplotype includes rs10766410 inthe OTOG gene, then the reference haplotype should also includers10766410 for comparison purposes; or if the test haplotype includesrs553042 in the CACNA1E gene, then the reference haplotype should alsoinclude rs553042 for comparison purposes. In methods where the haplotypeanalysis is performed to determine risk of developing SZ, the sharing ofa haplotype (e.g., of some or all of the marker alleles) between thetest haplotype and a reference haplotype is indicative of whether thereis an increased likelihood that the subject will develop SZ. Thereference haplotype can be from a relative, e.g., a first or seconddegree relative, or from an unrelated individual (or population), thathas been identified as either having or not having SZ, SD, or SPD.Optionally, a reference haplotype is also obtained from an unaffectedperson, e.g., an unaffected relative, and lack of sharing of a haplotypeof a haplotype between the test haplotype and the reference haplotypeindicates that the subject has an increased risk of developing SZ.

In methods where the haplotype analysis is performed to determine riskof having a particular endophenotype or endophenotype severity (e.g., onthe PANSS scale), the sharing of a haplotype (e.g., of some or all ofthe marker alleles) between the test haplotype and a reference haplotypeis indicative of whether there is an increased likelihood that thesubject will have an elevated (high) or low value for that specificendophenotype. For example, the reference haplotype can be from arelative, e.g., a first or second degree relative, or from an unrelatedindividual (or population), e.g., a person that has been diagnosed withSZ, and further identified as either having or not having an elevatedvalue for the specific endophenotype. In some embodiments, the presenceof the haplotype does not indicate the presence or absence of a specificphenotype, but rather the degree to which the phenotype occurs, e.g., onthe PANSS scale; as one example, alleles of the marker rs11030008 canimpact the severity of delusions and suspiciousness/persecution notnecessarily its presence or absence of these symptoms.

In methods where the haplotype analysis is performed to predict responseto a particular treatment, the sharing of a haplotype (e.g., of some orall of the marker alleles) between the test haplotype and a referencehaplotype is indicative of how the subject is likely to respond to thetreatment. For example, the reference haplotype can be from a relative,e.g., a first or second degree relative, or from an unrelated individual(or population), that has been diagnosed with SZ and further identifiedas responding positively (i.e., with an improvement in one or moresymptoms of the disease) or negatively (i.e., with no improvement, oreven a worsening, of one or more symptoms of the disease, or withexcessive side effects).

In some embodiments, the methods include administering a treatment to asubject identified as being at increased risk for developing SZ, e.g., apharmacological treatment as described herein. In some embodiments, thesubject has no overt or clinical signs of SZ, SD, or SPD, and thetreatment is administrated before any such signs appear.

Information obtained using a method described herein can be used, e.g.,to select a subject population for a clinical trial, to stratify asubject population in a clinical trial, and/or to stratify subjects thatrespond to a treatment from those who do not respond to a treatment, orsubjects that have negative side effects from those who do not.

In another aspect, the invention provides methods for selecting asubject for inclusion in a clinical trial, e.g., a trial of a treatmentfor SZ, SD, or SPD. The methods include obtaining a haplotype for thesubject including at least one marker that is found within the regiondelimited by SNP1 and SNP2, inclusive, for a given gene as specified inTable A, or comprising one or more of the exemplary SNP markers for eachgene, as specified in the Table B and/or SNP markers in linkagedisequilibrium with these markers e.g. as shown in the Examples;determining whether the haplotype is associated with an increased riskof developing SZ; and including the subject in the trial or excludingthe subject from the trial if the haplotype indicates that the subjecthas altered drug response for patients with SZ, SD, or SPD.

In another aspect, the invention provides methods for selecting asubject for administration of a treatment for schizophrenia (SZ). Themethods include obtaining a haplotype for the subject, wherein thehaplotype comprises at least one marker that is listed in Table B, or isin linkage disequilibrium with a marker listed in Table B, asexemplified by the Markers listed in Table C; determining whether thehaplotype is associated with altered (e.g., positive or negative)treatment response for patients with SZ; and administering the treatmentto the subject if the haplotype indicates that the subject has animproved response to the treatment. In another aspect, the inventionprovides methods for selecting a treatment for administration to asubject. The methods include obtaining a haplotype for the subject,wherein the haplotype comprises at least one marker that is listed inTable B, or is in linkage disequilibrium unit with a marker listed inTable B; determining whether the haplotype is associated with altered(e.g., positive or negative) treatment response for patients withschizophrenia (SZ); and administering the treatment for SZ to thesubject if the haplotype indicates that the subject has an improvedresponse to the treatment.

In another aspect, the invention provides methods for evaluating theeffect of a haplotype on the outcome of a treatment for schizophrenia(SZ). The methods include obtaining information regarding outcome of thetreatment, wherein the information comprises a parameter relating to thetreatment of each subject in a population of subjects; obtaininghaplotypes for each subject in the population, wherein the haplotypecomprises at least one marker that is listed in Table B, or is inlinkage disequilibrium with a marker listed in Table B; and correlatingthe information regarding outcome with the haplotypes; therebyevaluating the effect of the haplotype on the outcome of the treatment.

In some embodiments, the method includes selecting a treatment foradministration to a subject who has a selected haplotype, based on theeffect of the haplotype on the outcome of the treatment.

In some embodiments, the information regarding outcome of the treatmentis from a completed clinical trial, and the analysis is retrospective.

In a further aspect, the invention features methods for detecting thepresence of a haplotype associated with susceptibility to SZ (broadlydefined as including, in addition to narrowly defined SZ, SD or SPD) ina subject, by analyzing a sample of DNA from the subject.

Additionally, the invention features methods of predicting a testsubject's risk of developing SZ. The methods include obtaining areference haplotype of a reference subject, wherein the referencesubject has SZ, SD, or SPD; determining a test haplotype of the testsubject in the same region; and comparing the test haplotype to thereference haplotype, wherein the sharing of a haplotype in this regionbetween the test subject and the reference subject is an indication ofan increased likelihood that the test subject will develop SZ. In someembodiments, the method further includes comparing the subject'shaplotype to a reference subject who does not have SZ, SD, or SPD.

Further, the invention features methods for predicting a test subject'srisk of developing SZ. The methods include obtaining a referencehaplotype of a reference subject in a region described herein, whereinthe reference subject has SZ; obtaining a test haplotype of the testsubject in the same region; and comparing the test haplotype to thereference haplotype. The sharing of a haplotype in this region betweenthe test subject and the reference subject is an indication of anincreased likelihood that the test subject will develop SZ. In someembodiments, the method also includes comparing the test subject'shaplotype to a reference subject who does not have SZ.

Also provided herein are kits for use in detection of haplotypesassociated with SZ, including at least one nucleic acid probe thathybridizes to a sequence that includes a polymorphism described herein,or can be used to amplify a sequence that includes a polymorphismdescribed herein.

Also provided are arrays that include a substrate having a plurality ofaddressable areas, wherein one or more of the addressable areas includesone or more probes that can be used to detect a polymorphism describedherein.

In another aspect, the invention provides methods for providinginformation regarding a subject's risk of developing schizophrenia (SZ).The methods include obtaining a sample from the subject at a first site;transferring the sample to a second site for analysis, wherein theanalysis provides data regarding the identity, presence or absence of atleast one test marker that is that is found within the region delimitedby SNP1 and SNP2, inclusive, for a given gene as specified in Table A,or comprising one or more of the exemplary SNP markers for each gene, asspecified in the Examples and/or SNP markers in linkage disequilibriumwith these markers; and transferring the data to one or more of a healthcare provider, the subject, or a healthcare payer. In some embodiments,the first site is a health care provider's place of business, or is nota health care provider's place of business, e.g., the subject's home.

In some embodiments, the data is transferred to a healthcare payer andused to decide whether to reimburse a health care provider.

DEFINITIONS

As defined herein, “Schizophrenia” or “SZ” includes the SZ-spectrumdisorders, Schizotypal Personality Disorder (SPD) and SchizoaffectiveDisorder (SD), as well as Schizophrenia under the narrower, DSM-IVdefinition (see below).

As used herein, a “haplotype” is one or a set of signature geneticchanges (polymorphisms) that are normally grouped closely together onthe DNA strand, and are usually inherited as a group; the polymorphismsare also referred to herein as “markers.” A “haplotype” as used hereinis information regarding the presence or absence of one or morecontiguous genetic markers on a given chromosome in a subject. Ahaplotype can consist of a variety of genetic markers, including indels(insertions or deletions of the DNA at particular locations on thechromosome); single nucleotide polymorphisms (SNPs) in which aparticular nucleotide is changed; microsatellites; and minisatellites.

Microsatellites (sometimes referred to as a variable number of tandemrepeats or VNTRs) are short segments of DNA that have a repeatedsequence, usually about 2 to 5 nucleotides long (e.g., CACACA), thattend to occur in non-coding DNA. Changes in the microsatellitessometimes occur during the genetic recombination of sexual reproduction,increasing or decreasing the number of repeats found at an allele,changing the length of the allele. Microsatellite markers are stable,polymorphic, easily analyzed and occur regularly throughout the genome,making them especially suitable for genetic analysis.

“Linkage disequilibrium” occurs when the observed frequencies ofassociations of alleles for different polymorphisms in a population donot agree with frequencies predicted by multiplying together the allelefrequencies for the individual genetic markers, thus resulting in aspecific haplotype in the population.

The term “chromosome” as used herein refers to a gene carrier of a cellthat is derived from chromatin and comprises DNA and protein components(e.g., histones). The conventional internationally recognized individualhuman genome chromosome numbering identification system is employedherein. The size of an individual chromosome can vary from one type toanother with a given multi-chromosomal genome and from one genome toanother. In the case of the human genome, the entire DNA mass of a givenchromosome is usually greater than about 100,000,000 base pairs. Forexample, the size of the entire human genome is about 3×10⁹ base pairs.

The term “gene” refers to a DNA sequence in a chromosome that codes fora product (either RNA or its translation product, a polypeptide). A genecontains a coding region and includes regions preceding and followingthe coding region (termed respectively “leader” and “trailer”). Thecoding region is comprised of a plurality of coding segments (“exons”)and intervening sequences (“introns”) between individual codingsegments.

The term “probe” refers to an oligonucleotide. A probe can be singlestranded at the time of hybridization to a target. As used herein,probes include primers, i.e., oligonucleotides that can be used to primea reaction, e.g., a PCR reaction.

The term “label” or “label containing moiety” refers in a moiety capableof detection, such as a radioactive isotope or group containing same,and nonisotopic labels, such as enzymes, biotin, avidin, streptavidin,digoxygenin, luminescent agents, dyes, haptens, and the like.Luminescent agents, depending upon the source of exciting energy, can beclassified as radioluminescent, chemiluminescent, bioluminescent, andphotoluminescent (including fluorescent and phosphorescent). A probedescribed herein can be bound, e.g., chemically bound tolabel-containing moieties or can be suitable to be so bound. The probecan be directly or indirectly labeled.

The term “direct label probe” (or “directly labeled probe”) refers to anucleic acid probe whose label after hybrid formation with a target isdetectable without further reactive processing of hybrid. The term“indirect label probe” (or “indirectly labeled probe”) refers to anucleic acid probe whose label after hybrid formation with a target isfurther reacted in subsequent processing with one or more reagents toassociate therewith one or more moieties that finally result in adetectable entity.

The terms “target,” “DNA target,” or “DNA target region” refers to anucleotide sequence that occurs at a specific chromosomal location. Eachsuch sequence or portion is preferably at least partially, singlestranded (e.g., denatured) at the time of hybridization. When the targetnucleotide sequences are located only in a single region or fraction ofa given chromosome, the term “target region” is sometimes used. Targetsfor hybridization can be derived from specimens which include, but arenot limited to, chromosomes or regions of chromosomes in normal,diseased or malignant human cells, either interphase or at any state ofmeiosis or mitosis, and either extracted or derived from living orpostmortem tissues, organs or fluids; germinal cells including sperm andegg cells, or cells from zygotes, fetuses, or embryos, or chorionic oramniotic cells, or cells from any other germinating body; cells grown invitro, from either long-term or short-term culture, and either normal,immortalized or transformed; inter- or intraspecific hybrids ofdifferent types of cells or differentiation states of these cells;individual chromosomes or portions of chromosomes, or translocated,deleted or other damaged chromosomes, isolated by any of a number ofmeans known to those with skill in the art, including libraries of suchchromosomes cloned and propagated in prokaryotic or other cloningvectors, or amplified in vitro by means well known to those with skill;or any forensic material, including but not limited to blood, or othersamples.

The term “hybrid” refers to the product of a hybridization procedurebetween a probe and a target.

The term “hybridizing conditions” has general reference to thecombinations of conditions that are employable in a given hybridizationprocedure to produce hybrids, such conditions typically involvingcontrolled temperature, liquid phase, and contact between a probe (orprobe composition) and a target. Conveniently and preferably, at leastone denaturation step precedes a step wherein a probe or probecomposition is contacted with a target. Guidance for performinghybridization reactions can be found in Ausubel et al., CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y. (2003),6.3.1-6.3.6. Aqueous and nonaqueous methods are described in thatreference and either can be used. Hybridization conditions referred toherein are a 50% formamide, 2×SSC wash for 10 minutes at 45° C. followedby a 2×SSC wash for 10 minutes at 37° C.

Calculations of “identity” between two sequences can be performed asfollows. The sequences are aligned for optimal comparison purposes(e.g., gaps can be introduced in one or both of a first and a secondnucleic acid sequence for optimal alignment and non-identical sequencescan be disregarded for comparison purposes). The length of a sequencealigned for comparison purposes is at least 30%, e.g., at least 40%,50%, 60%, 70%, 80%, 90% or 100%, of the length of the referencesequence. The nucleotides at corresponding nucleotide positions are thencompared. When a position in the first sequence is occupied by the samenucleotide as the corresponding position in the second sequence, thenthe molecules are identical at that position. The percent identitybetween the two sequences is a function of the number of identicalpositions shared by the sequences, taking into account the number ofgaps, and the length of each gap, which need to be introduced foroptimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In some embodiments, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package, using a Blossum 62 scoring matrix with a gap penaltyof 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

As used herein, the term “substantially identical” is used to refer to afirst nucleotide sequence that contains a sufficient number of identicalnucleotides to a second nucleotide sequence such that the first andsecond nucleotide sequences have similar activities. Nucleotidesequences that are substantially identical are at least 80%, e.g., 85%,90%, 95%, 97% or more, identical.

The term “nonspecific binding DNA” refers to DNA which is complementaryto DNA segments of a probe, which DNA occurs in at least one otherposition in a genome, outside of a selected chromosomal target regionwithin that genome. An example of nonspecific binding DNA comprises aclass of DNA repeated segments whose members commonly occur in more thanone chromosome or chromosome region. Such common repetitive segmentstend to hybridize to a greater extent than other DNA segments that arepresent in probe composition.

As used herein, the term “stratification” refers to the creation of adistinction between subjects on the basis of a characteristic orcharacteristics of the subjects. Generally, in the context of clinicaltrials, the distinction is used to distinguish responses or effects indifferent sets of patients distinguished according to the stratificationparameters. In some embodiments, stratification includes distinction ofsubject groups based on the presence or absence of particular markers orhaplotypes described herein. The stratification can be performed, e.g.,in the course of analysis, or can be used in creation of distinct groupsor in other ways.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-C is a list of exemplary genes useful in the methods describedherein, with the sequence identifiers from the GenBank database fortheir genomic sequences.

DETAILED DESCRIPTION

The present inventors have used bioinformatics and genetic linkages forrelated neuropsychiatric endophenotypes and DSM disease definitions todefine genes in common cellular pathways across various chromosomes ashigh priority targets for TDT and Case/Control analysis. Resources ofthe International HapMap project (hapmap.org) were used to define SNPsin these loci, whose pattern of transmission in families and diseaseassociation in the population captures extant genetic variation(including important coding variation if present) contributing togenetic susceptibility to SZ-spectrum disorders.

The invention includes methods for assessing genetic risk, aiding indiagnosis, and/or stratifying patient populations in order to selectoptimal treatments based on evaluation of single nucleotidepolymorphisms (SNPs) for a number of bioinformatically identified geneson chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or20 relating to SZ-spectrum disorders including narrowly definedschizophrenia, schizotypal personality disorder (SPD) andschizoaffective disorder (SD) (collectively referred to herein as “SZ”).Specific SNPs delimiting each gene (delimiting SNPs) are given alongwith exemplary SNPs can be used to capture significant haplotypevariation in these genes. Important variants can be verified via TDTusing families with multiple affected individuals (such as thosecollected CCGS) and by Case/Control comparisons using the SNP markerspresented herein. Using SNP markers lying between the delimiting SNPs,inclusive, and identical to or in linkage disequilibrium with theexemplary SNPs, one can determine the haplotypes in these genes relatingto genetic risk of developing SZ-spectrum disorders via family-basedassociation analyses. These haplotypes can then be used to determinerisk of developing these disorders by Case/Control studies. The allelicand genotypic variants thus identified can be used for assessing geneticrisk, to aid in diagnosis, and/or to stratify patient population inorder to select optimal treatments (atypical antipsychotic, typicalantipsychotic, and/or psychosocial intervention) for patients.

Methods of Evaluating Susceptibility to SZ, Pharmacological Response,and Psychiatric Endophenotypes

Described herein are a variety of methods for the determination of asubject's risk of developing SZ (which can also be consideredsusceptibility to SZ) and related clinical phenotypes, likelihood orrisk of having an specific endophenotype or severity of anendophenotype, and for predicting a subject's response to a treatmentfor SZ.

“Susceptibility” to SZ does not necessarily mean that the subject willdevelop SZ, but rather that the subject is, in a statistical sense, morelikely to develop SZ than an average member of the population, i.e., hasan increased risk of developing SZ. As used herein, susceptibility to SZexists if the subject has a haplotype associated with an increased riskof SZ as described herein. Ascertaining whether the subject has such ahaplotype is included in the concept of diagnosing susceptibility to SZas used herein. Similarly, susceptibility to displaying a particularclinical phenotype does not mean that the subject will have thephenotype, but rather that the subject is, in a statistical sense, morelikely to display the phenotype. Thus, the methods described herein caninclude obtaining a haplotype associated with an increased risk ofhaving a specific clinical phenotype as described herein for thesubject. Furthermore, a prediction of response may not provide 100%certainty, but simply a statistical likelihood that the subject willrespond in a particular way to a particular treatment. Suchdeterminations are useful, for example, for purposes of diagnosis,treatment selection, and genetic counseling.

As used herein, “obtaining a haplotype” includes obtaining informationregarding the identity, presence or absence of one or more geneticmarkers in a subject. Obtaining a haplotype can, but need not, includeobtaining a sample comprising DNA from a subject, and/or assessing theidentity, presence or absence of one or more genetic markers in thesample. The individual or organization who obtains the haplotype neednot actually carry out the physical analysis of a sample from a subject;the haplotype can include information obtained by analysis of the sampleby a third party. Thus the methods can include steps that occur at morethan one site. For example, a sample can be obtained from a subject at afirst site, such as at a health care provider, or at the subject's homein the case of a self-testing kit. The sample can be analyzed at thesame or a second site, e.g., at a laboratory or other testing facility.Obtaining a haplotype can also include or consist of reviewing asubject's medical history, where the medical history includesinformation regarding the identity, presence or absence of one or moregenetic markers in the subject, e.g., results of a genetic test.

As described herein, haplotypes associated with SZ include specificalleles for markers in Tables B and C, and makers in linkagedisequilibrium with these, as exemplified by the Case/Control results inTable 1.

As one example, haplotypes associated with pharmacological responseinclude one or more markers in Tables B and C and/or markers in linkagedisequilibrium with these markers as exemplified by the Examples inTables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13. Haplotypes associatedwith response to olanzapine can include one or more markers listed inTables 2 and 3 and/or markers in linkage disequilibrium with thesemarkers. Haplotypes associated with response to risperidone can includeone or more markers listed in Tables 4 and 5 and/or markers linkagedisequilibrium with these markers. Haplotypes associated with responseto quetiapine can include one or more markers listed in Tables 6 and 7and/or markers linkage disequilibrium with these markers. Haplotypesassociated with response to perphenazine can include one or more markerslisted in Tables 8 and 9 and/or markers linkage disequilibrium withthese markers. Haplotypes associated with response to ziprasidone caninclude one or more markers listed in Tables 10 and 11 and/or markerslinkage disequilibrium with these markers. Haplotypes associated withresponse to antipsychotic medications, as a group, can include one ormore markers listed in Tables 12 and 13 and/or markers linkagedisequilibrium with these markers. In some embodiments, the haplotypeincludes one or more of the markers listed in Tables 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13.

As another example, haplotypes associated with specific psychiatricendophenotypes include one or more markers in Tables B and C and/ormarkers in linkage disequilibrium with these markers as exemplified bythe Examples in Tables 14 and 15 and/or markers linkage disequilibriumwith these markers. Haplotypes associated with altered scores for themain subscales of the Positive and Negative Syndrome Scale (PANSS) caninclude one or more markers listed in Table 14. Haplotypes associatedwith altered scores for specific subscales of the PANSS can include oneor more markers listed in Table 15 and/or markers in linkagedisequilibrium with these markers. In some embodiments, the haplotypeincludes one or more of the markers listed in Tables 14 and 15.

In some embodiments, to detect the presence of a haplotype describedherein, a biological sample that includes nucleated cells (such asblood, a cheek swab or mouthwash) is prepared and analyzed for thepresence or absence of preselected markers. Such diagnoses may beperformed by diagnostic laboratories, or, alternatively, diagnostic kitscan be manufactured and sold to health care providers or to privateindividuals for self-diagnosis. Diagnostic or prognostic tests can beperformed as described herein or using well known techniques, such asdescribed in U.S. Pat. No. 5,800,998.

Results of these tests, and optionally interpretive information, can bereturned to the subject, the health care provider or to a third partypayor. The results can be used in a number of ways. The information canbe, e.g., communicated to the tested subject, e.g., with a prognosis andoptionally interpretive materials that help the subject understand thetest results and prognosis. The information can be used, e.g., by ahealth care provider, to determine whether to administer a specificdrug, or whether a subject should be assigned to a specific category,e.g., a category associated with a specific disease endophenotype, orwith drug response or non-response. The information can be used, e.g.,by a third party payor such as a healthcare payer (e.g., insurancecompany or HMO) or other agency, to determine whether or not toreimburse a health care provider for services to the subject, or whetherto approve the provision of services to the subject. For example, thehealthcare payer may decide to reimburse a health care provider fortreatments for SZ, SPD, or SD if the subject has an increased risk ofdeveloping SZ. As another example, a drug or treatment may be indicatedfor individuals with a certain haplotype, and the insurance companywould only reimburse the health care provider (or the insuredindividual) for prescription or purchase of the drug if the insuredindividual has that haplotype. The presence or absence of the haplotypein a patient may be ascertained by using any of the methods describedherein.

Information obtained from the methods described herein can also be usedto select or stratify subjects for a clinical trial. For example, thepresence of a selected haplotype described herein can be used to selecta subject for a trial. The information can optionally be correlated withclinical information about the subject, e.g., diagnostic, therapeutic,or endophenotypic information.

Haplotypes Associated with SZ, Pharmacological Response, and PsychiatricEndophenotypes

The methods described herein include the analysis of genotypicinformation for exemplary SNPs described herein as being associated withincreased risk of developing SZ, pharmacological response, and havingspecific psychiatric endophenotypes. The methods can also (oralternatively) include the evaluation of SNPs that are in linkagedisequilibrium with the exemplary SNPs (as one of skill in the art willappreciate, those SNPs that are in linkage disequilibrium will provideessentially the same information as the exemplary SNPs). In someembodiments, the methods include the use of SNPs that are in linkagedisequilibrium and are within a specified region of the gene. Table Bincludes exemplary delimiting SNPs and exemplary test SNPs that can beused in capturing significant haplotype variation in these genes.Although exemplary delimiting SNPs are provided, in some embodiments theregion can be delimited by one of the other SNPs listed herein, e.g., anexemplary test SNP that is in LD with the primary SNP. In someembodiments, the specific region of the gene is between and excludingthe delimiting SNPs; in some embodiments, the specific region is betweenand including the delimiting SNPs.

TABLE B Delimiting and Exemplary SNPs for Novel SZ Genes Gene CHRDelimiting SNPs Exemplary SNPS Potassium Channel and Related Genes KCNC41 rs1359149 to rs11578913 rs615204, rs34171476, rs35167146 KCNA10 1rs1281177 to rs17025957 rs1281175, rs34970857, rs1281174, rs3768456KCND3 1 rs197422 to rs10745323 rs12033257, rs35027371, rs3738298,rs11102342, rs4838924, rs4839183, rs17215423, rs2289723, rs3820673,rs1936061 KCNH1 1 rs12126648 to rs1538287 rs3135473, rs1135317,rs1770213, rs1770220, rs11119627, rs1501569, rs1393026, rs11119658,rs4620600, rs4578265, rs867848, ANK3 10 rs1050745 to rs1551684rs1049862, rs7911953, rs2393607, rs12261793, rs10733757, rs7907721,rs4568956, rs2241540, rs2393596, rs11596260, rs3750800, rs10218875,rs4948254, rs6479694 KCNQ1 11 rs11022827 to rs2239897 rs2283155,rs6578273, rs34320941, rs4930127, rs2283174, rs45478697, rs45606931,rs45497392, rs231348, rs17215465, rs760419, rs231899, rs63934,rs45603932, rs1057128, rs81205, rs45594640, rs34516117, rs1800172,rs34150427, rs11601907, rs8234 KCNC1 11 rs7949069 to rs1236205rs2299637, rs4757587, rs757514, rs10766434, rs7942518 Cell Adhesion andRelated Genes RP1-21O18.1 1 rs9663010 to rs2235789 rs7546786, rs6663699,rs1316257, rs938249, rs6674129, rs2073091, rs2076563, rs12057431,rs4661572 CTNND1 11 rs558653 to rs652908 rs2156638, rs11570176,rs10896644, rs11570194, rs483030, rs11570199, rs612688, rs11570222,rs708228 DACT1 14 rs464582 to rs160472 rs167481, rs150722, rs167481,rs863091,, rs34015825, rs17832998, rs17094821, rs698025, rs11541 CDH1116 rs35148 to rs7204464 rs35147, rs35145978, rs35144, rs35229, rs35213,rs4424934, rs35195, rs35186, rs1520233, rs7188625 Vesicle Related GenesVAMP4 1 rs10913508 to rs7556644 rs15655, rs15655, rs10913530, rs2073484,rs6672082, rs12096984 SYT14 1 rs9429830 to rs11119426 rs227221,rs4844923, rs2205989, rs11119392, rs227227, rs2307890, rs11119415,rs17188183, rs4609425 BRSK2 11 rs7395835 to rs1554857 rs10833086,rs7932863, rs9651643, rs34893167, rs1881504, rs11029039, rs3829225,rs1574122 SYT13 11 rs2863172 to rs11038382 rs4992029, rs8929, rs2863174,rs4755941, rs7103871, rs12362429, rs2863182 STX2 12 rs2632601 tors7962097 rs6486602, rs1236, rs4759517, rs2277336, rs6486600, rs4759794,rs7301926, rs6486602, rs10848210, rs10848210 RTN1 14 rs17255975 tors7144589 rs7161094, rs1950785, rs4898998, rs12717467, rs34431036,rs35707243, rs35645652, rs35645652, rs35864480, rs10145080, rs17310036UNC13C 15 rs11071015 to rs9920150 rs17731958, rs2115827, rs2163195,rs12594549, rs1897069, rs12910912, rs12910912, rs11856476, rs4776216,rs7183952, rs12917364, rs12914912, rs8035356, rs1158075, rs1849210,rs12913366, rs489526, rs8025195, rs16974691, rs9302181, rs11639005,rs1520411, rs9920139 SV2B 15 rs11630131 to rs7169918 rs2073967,rs35575298, rs8027498, rs1075840, rs16945475, rs2301665, rs3743444,rs1117388, rs1117388, rs16945529 Genes Related to Glutamate PathwaysGcom1 15 rs1908202 to rs1808478 rs4774275, rs1908206, rs2470357,rs2069133,, rs16977629, rs16977631, rs986868, rs2733617, rs16977644,rs2733619, rs2470361, rs11854917 GRINL1A 15 rs1908202 to rs1808478rs4774275, rs1908206, rs2470357, rs2069133,, rs16977629, rs16977631,rs986868, rs2733617, rs16977644, rs2733619, rs2470361, rs11854917 GOT216 rs2042445 to rs4238801 rs30839, rs6993, rs30842, rs11076256,rs257636, rs257620 G-Protein-Coupled Receptor Genes RHOG 11 rs1055640 tors4406820 rs1451722, rs17173879, rs1049388, rs1451719, rs11030008 GPR13514 rs17255731 to rs4898989 rs1612112, rs1253181, rs10138199, rs9323348,rs1752427, rs1752428, rs10136708 AKAP13 15 rs1533124 to rs11637212rs16977252, rs8024200, rs7180213, rs6497206, rs2291049, rs2061821, U171,rs2061822, rs34434221, rs2061824, rs745191, rs7177107, rs7177107,rs4075256, rs4075254, rs4843074, rs4843075, rs7162168, rs4842895,rs35079107, rs338523, rs338556, rs11073502, rs11073502, rs2241268,rs2241268, rs1053992 Delimiting SNPs for Hormone, Inositol, andDiacylglyceride Related Genes HSD17B12 11 rs12364003 to rs11037691rs4573669, rs10838160, rs4755744, rs7129046, rs3802891, rs11555762,rs1061810 TMEM55B 14 rs1130409 to rs1760941 rs17112002, rs1760943,rs35567022 IGF1R 15 rs35554027 to rs702497 rs8028620, rs7170035,rs7174918, rs8038015, rs4966020, rs4965436, rs8030950, rs1879613,rs11247380, rs45445894, rs34516635, rs33958176,, rs33958176, rs45553041,rs2684808, rs3743262, rs1546713, rs2229765, rs2684792, rs17847203,rs3833015 Cytoskeletal, Myosin, Actin and Microtubulal Related Genes EVL14 rs1190954 to rs35257667 rs748354, rs1190956, rs1190974, rs3206354,rs726514, rs941897, rs34073270, rs4905933 KATNAL2 18 rs9304340 tors1434528 rs2576042, rs2187092, rs2571030, rs2247221, rs7233515,rs9961383, rs2289130 Genes for Carrier Proteins and Transporters SLC6A171 rs924181 to rs545849 rs877068, rs1010892, rs6689641, rs534276,rs534276, rs6685009, rs12133992 SLC16A4 1 rs10857820 to rs12127781rs2946571, rs11120, rs6673423, rs2271885, rs35157487, rs3738750,rs1334882, rs884684 SLC6A5 11 rs894747 to rs1401793 rs2001982,rs2241940, rs1443547, rs7109418, rs1443548, rs34243519, rs894750,rs4923386, rs16906566, rs11827415, rs3740870, rs1805091, rs7944684,rs2298826, rs2276433, rs16906628, rs1401793 SLC17A6 11 rs1155821 tors2593644 rs2246710, rs11026523, rs2078352, rs11026532, rs1900586,rs764021, rs7117340, rs1979072, rs1979073 SLCO3A1 15 rs11858120 tors1060206 rs12907294, rs4294800, rs2176452, rs12912997, rs1878556,rs2286355, rs1517618, rs6496893, rs2074887, rs2302085, rs8174 Cell Cycleand Tumor Suppressor/Promoter Related Genes RERE 1 rs1055236 to rs914994rs8627, rs1058766, rs13596, rs3753275, rs7530745, rs12136689, rs7532459,rs7554486, rs6698830 FASLG 1 rs763110 to rs12135884 rs929087, rs6700734,rs10458360, rs35178418 DEAF1 11 rs936465 to rs6597990 rs11822917,rs34114147, rs7109335, rs10902188, rs6597996, rs34094369, rs7935419,rs7121608, rs4963145 HCCA2 11 rs12786504 to rs2334652 rs7945160, rs9440,rs10219175, rs7396514, rs7945160, rs10742185 PTPN5 11 rs873670 tors7932938 rs7946105, rs1550871, rs1550870, rs6483524, rs4757707,rs10766500, rs4272766, rs4274187, rs4345940 CHFR 12 rs1531822 tors3741494 rs3741489, rs3741492, rs2306536, rs2306537, rs9634239,rs2306541, rs4758954, rs35206714, rs34220055, rs2291253, rs11147144 TTC514 rs10130942 to rs10873395 rs10147548, rs3737220, rs1953552, rs3742945,rs34675160, rs2318864 FUSSEL18 18 rs2137289 to rs892583 rs7236105,rs17785419, rs10502880, rs2668771 SMAD2 18 rs1792666 to rs2000709rs7228393, rs1792682, rs17340985, rs1787176, rs1942158, rs12457664 SMAD718 rs9944944 to rs736839 rs11874392, rs8088297, rs34151545, rs11874392,rs1873190, rs3736242 SMAD4 18 rs620898 to rs12456284 rs3764465,rs12958604, rs2276163, rs12458752, rs2298617 Genes Involved in NeuronalDevelopment and Plasticity DNM3 1 rs6701033 to rs13932 rs965051,rs2206543, rs7554526, rs2093184, rs3736790, rs10489730, rs3736791,rs3736791, rs4576686, rs4075021, rs4382763, rs34870740, rs9425287,rs2301454, rs10752946, rs7528296 TOLLIP 11 rs5744038 to rs5743854rs3750920, rs3168046, rs35365323, rs5744015, rs5743899 DUSP8 11rs6578504 to rs10734456 rs3740620, rs2008493, rs7934037, rs3740620,rs3740620, rs902224, rs902225 NAV2 11 rs890136 to rs2246192 rs2278132,rs2042600, rs10766590, rs7119267, rs6483617, rs16937196, rs2585788,rs11025310, rs7935182, rs16937251, rs1372989, rs10833202, rs11025335,rs12284679, rs2707084, rs6483629, rs3802799, rs3802800, rs7125647,rs1442710, rs1867114, rs2028570, rs2289566, rs35891966, rs3802803 LRRC4C11 rs11035693 to rs10128639 rs998447, rs2953310, rs1551833, rs6485187,rs10837367, rs998447, rs3802787 RTN4RL2 11 rs2729363 to rs2955849rs2511986, rs3851117 DTX4 11 rs10896947 to rs544864 rs6591507,rs6591507, rs656163, rs2211912, rs621162, rs1048444, rs3847, rs5029315ULK1 12 rs11246867 to rs7978708 rs3088051, rs9652059, rs11616018,rs12303764, rs11609348, rs3088051, rs3088051 NDRG2 14 rs1263871 tors1243451 rs10196, rs1243444, rs1243446, rs1243446, rs1243450,rs10138807 JPH4 14 rs12897422 to rs222732 rs11844366, rs10149510,rs10149510, rs10150089 DAAM1 14 rs17095965 to rs4127823 rs17095965,rs17833769, rs1252989, rs1268579, rs4901909, rs1253005, rs4898983,rs10143918, rs12147707, rs8022614, rs941884, rs1958180, rs941886,rs11626926, rs10083442 NEDD4 15 rs4424863 to rs1509408 rs3088077,rs17238461, rs8028559, rs34478706, rs12232351, rs2303579, rs2303580,rs1912402, rs16976618, rs2271289, rs1553739, rs11632974 RGMA 15rs12438714 to rs4114 rs2272453, rs13167, rs1997382, rs2091635, rs6497019N4BP1 16 rs9937623 to rs9936446 rs3826176, rs1224, rs1039342, rs3826176,rs1120276, rs2354580 NDRG4 16 rs7202037 to rs2280397 rs13333449,rs2042405, rs2271948, rs2271948, rs42945, rs1058132 CDH8 16 rs4131634 tors9302540 rs16963768, rs16963771, rs4636897, rs9922048, rs11862141,rs6498807, rs9939991, rs1369918, rs1978796, rs11075445, rs1397131,rs8057338 BEAN 16 rs6499082 to rs12445633 rs11644279, rs34695237,rs4247350 KIAA0513 16 rs1875246 to rs1466864 rs7499978, rs3803637,rs4783121, rs12597135, rs12446708, rs3794684, rs3751756 DYM 18 rs1288812to rs17725481 rs833503, rs357894, rs8096141, rs8092003, rs2276200,rs523373, rs498929, rs35435872, rs10775493, rs1943675 DCC 18 rs17753970to rs2270954 49311296, rs11875475, rs1145245, rs1465943, rs6508145,rs8089980, rs13381333, rs1893572, rs1431748, rs2229080, rs950278,rs8096519, rs7506904, rs12457407, rs4940251, rs8097413, rs2278339,rs1393331, rs984274, rs984274, rs6508235 BMP7 20 rs6014947 to rs2208404rs162316, rs10375, rs3787381, rs230198, rs193044, rs6025469 TMEPAI 20rs6025689 to rs6015068 rs6025698, rs427278, rs13043471, rs4811905Calcium/Calmodulin Related Genes CAMTA1 1 rs449250 to rs228651rs10864639, rs12044121, rs6688732, rs6577393, rs7554752, rs6577401,rs12070592, rs2067995, rs845197, rs1193219, rs1011124, rs6696544,rs12751990, rs3737907, rs3737906, rs4908473, rs1417986, rs2071986,rs707455 CACNA1E 1 rs541886 to rs635118 rs553042, rs17494681, rs506947,rs3856090, rs199960, rs3766980, rs35606457, rs35737760, rs34488539,rs4652678, rs199930, rs704326, rs638132 CAMK1G 1 rs17014820 to rs926387rs2356933, rs6690557, rs9430004, rs35618105, rs11119314, rs11119315,rs2272879, rs2206107, rs4140599, rs2076230 RIMBP2 12 rs1496858 tors7963990 rs10848094, rs756186, rs749093, rs11060869, rs7303240,rs2277356, rs2292663, rs2292664, rs7952756, rs2277361, rs871568,rs4237817, rs4759708 Genes Involved in Hereditary Hearing Loss DPH3 3rs2292614 to rs2245708 rs859703, rs842257, rs2245721, rs2245708 EXOC2 6rs10900954 to rs13205146 rs11242914, rs12952, rs4072107, rs1473909,rs2493037, rs2064302, rs2277095, rs2493049, rs2294660, rs2294664,rs998777, rs35600069, rs17756886, rs1747599, rs2039713 USH1C 11rs4756895 to rs2073582 rs2237965, rs1055577, rs1055574, rs2072225,rs1064074, rs34077456, rs10832796, rs16770, rs10766408, rs2240487,rs35336155, rs2041027, rs2237957 OTOG 11 rs2073582 to rs11024358rs10766410, rs11823045, rs7130190, rs11024323, rs7112749, rs7106548,rs4757548, rs2355466, rs11024333, rs7936324, rs7936354, rs11024335,rs2041028, rs1003490, rs7111528, rs11024350, rs12422210, rs10832824,rs2023483, rs11024357 SERGEF 11 rs1236205 to rs1133758 rs10788, rs1528,rs4757589, rs2237930, rs211146, rs2283233, rs211130, rs172424, rs211137,rs34960078, rs2237908 EML1 14 rs10140193 to rs7149272 rs10144785,rs7143905, rs12433613, rs11160553, rs6575751, rs746698, rs7144394,rs2273707, rs34198557, rs2250718, rs2273704, rs11160563 PMP22 17rs230938 to rs179521 rs231018, rs13422, rs7215851, rs231021 GenesEncoding Zinc-Finger Proteins PRDM2 1 rs2487657 to rs979932 rs1203682,rs1203677, rs2076324, rs17350795, rs1203648 ZFP91-CNTF 11 rs1944055 tors4319530 rs1938596, rs948562, rs7945889, rs8373, rs1938596, rs11229545ZNF423 16 rs193907 to rs12443775 rs729805, rs1344529, rs2287314,rs12597210, rs16947716, rs34611339, rs34214571, rs34214571, rs12924119,rs2292155, rs10852603, rs8060387 Brain-Expressed Genes Not OtherwiseSpecified PER3 1 rs172933 to rs707472 rs2797685, rs707463, rs707465,rs35426314, rs228669, rs17031601, rs10462020, rs35604043, rs35687686,rs35899625, rs228697, rs2640909, rs10462021 RABGAP1L 1 rs6681627 tors12126129 rs6425302, rs6425305, rs16847624 PHACS 11 rs178512 tors2285029 rs16937817, rs2074038, rs33952257, rs2018795, rs178521,rs35514614, rs2074043, rs7950395, rs178529, rs3107275 YPEL4 11 rs1798177to rs1647394 rs7947357, rs890036, rs12793139, rs7947357, rs12294735KIAA1853 12 rs7979864 to rs722307 rs1568923, rs6490226, rs1405049,rs4766926, rs7134748, rs7969288, rs10849629, rs12422371, rs7297606,rs7136574, rs2723880, rs2723882, rs2555269, rs1541764 KIAA1545 12rs10870551 to rs7294615 rs36098511, rs7137911, rs2323991, rs4883568,rs4883556, rs3751315, rs10870472, rs4883513, rs11208 TEP1 14 rs1713418to rs1760890 rs2104978, rs938886, rs1713449, rs34811735, rs35929175,rs35165628, rs7150689, rs34895824, rs2297615, rs35517499, rs938887,rs34401320, rs1713456, rs1713457, rs2229100, rs1760904, rs2228041,rs1713458, rs1760903, rs34179031, rs17111188, rs2228035, rs34770935,rs1760898, rs1760897, WDR25 14 rs2273802 to rs10151709 rs2273801,,,rs34007610, rs34331240, rs2273800, rs3742387, rs941924, rs4905966,rs10873518, rs4905969, rs4905969 BEGAIN 14 rs11628965 to rs7140556rs11845025, rs12893951, rs35286207, rs4073549, rs4074037, rs6575793HERC2 15 rs7495174 to rs1614575 rs1129038, rs11074322, rs11636232,rs1133496, rs1133496, rs4073541, rs2238289, rs3940272, rs11631797,rs916977, rs1635168, rs1635163 ADAM10 15 rs3764196 to rs514049rs6494032, rs12592750, rs7166076, rs8039791, rs12899638, rs7165402,rs12912286, rs4775086, rs2054096, rs653765 KLHL25 15 rs11637212 tors7181017 rs2614676, rs2554, rs3743335, rs2430838, rs36031133,rs35582838, rs11073537, rs2002909, rs2946365 NETO2 16 rs1551188 tors7184206 rs16952126, rs16952126, rs9923731, rs11859615, rs3095622 CBLN116 rs3743777 to rs9935379 rs11076478, rs1510977, rs1437105 KIAA0182 16rs4240810 to rs3815795 rs35869664, rs3815794, rs736845, rs2303203,rs9940601, rs1049868 C16orf74 16 rs11644122 to rs301143 rs373835,rs2305357, rs386061, rs408988 COX10 17 rs4792434 to rs7218697 rs2302107,rs16948978, rs34342426, rs16948986, rs8077302, rs2159132, rs8070339,rs2230354, rs11078233 KIAA0427 18 rs1039989 to rs752151 rs2175565,rs7229395, rs2306514, rs2277712, rs8094634, rs10853569, rs8095199,rs1038308, rs4939813, rs3764481, rs937021Additionally, a number of exemplary SNPs in linkage disequilibrium withthe SNPs in Table B were evaluated for impact on SZ risk,pharmacological response, and specific psychiatric phenotypes(endophenotypes). These exemplary SNPs in linkage disequilibrium withthose in Table B are listed in Table C.

TABLE C Exemplary SNPs in Linkage Disequilibrium with Table B SNPs GeneSNPs in linkage disequilibrium with those in Table B ADAM10 rs7164844,rs7161889, rs605928 AKAP13 rs12440599, rs2291048, rs2241268, rs16949988,rs2430838, rs870689, rs2241269, rs2241266, rs8025135, rs10520596,rs16941653, rs17623915, rs745191 ANK3 rs11596260, rs10761451,rs10761446, rs1551683, rs2393602, rs1078534, rs1050745 BEAN rs11075635,rs1063438 BMP7 rs6123669, rs6127980, rs162313, rs230191, rs230198 BRSK2rs1108991, rs1554857, rs7396009 C16orf74 rs442069, rs394623, rs386061,rs11644122 CACNA1E rs17494681, rs16857457, rs678643, rs553042,rs7513540, rs3856093, rs10797729, rs7554158, rs1953690, rs7534913,rs704331, rs17693196, rs546191 CAMK1G rs10489339, rs7516885, rs9429821,rs713075, rs7512091, rs6683256 CAMTA1 rs1616122, rs277675, rs17030082,rs845265, rs2097518, rs9919223, rs707463, rs697686, rs2301488,rs10864255, rs2071918, rs9434833, rs6698901, rs4908575, rs6657847,rs11121029, rs4243823 CBLN1 rs9935379, rs12598711, rs1469906, rs893175CDH11 rs35216, rs35195, rs35186, rs35144, rs40115, rs35140, rs4625747,rs35164, rs35162, rs35165, rs4967886 CDH8 rs11075445, rs1397126,rs13336134, rs9302540, rs9925201, rs7189354, rs4784163, rs6498806,rs4416006, rs16964164, rs11641508, rs11862752 CHFR rs4758911,rs11147101, rs7297261 COX10 rs8077302, rs1003060 CTNND1 rs1786438 DAAM1rs7143953, rs10873113, rs8004164, rs10483710, rs1271513, rs941886,rs4901909, rs12590850, rs1958180, rs1547199, rs12589351, rs4901921,rs2053298, rs1957409, rs6573250, rs2099636, rs17096088 DACT1 rs863091DCC rs1031062, rs882333, rs4998815, rs12967277, rs7228674, rs9954344,rs7506909, rs2270954, rs9949949, rs11082964, rs2036415, rs8089980,rs9966074, rs10515959, rs17504520, rs11876282, rs1502229, rs4940259,rs12605899, rs17506154, rs8088048, rs16954731, rs7504750, rs9953016,rs9807201, rs10853622, rs10853621, rs12455180, rs10502969 DEAF1rs10902190, rs936465, rs7123677 DNM3 rs6690848, rs9425606, rs9425598,rs4072117, rs12410416, rs12075807, rs10910966, rs7540873, rs1063412,rs6701929, rs7550558, rs2586389, rs2586392, rs10158839 DPH3 rs842252,rs842264, rs842261, rs2470508, rs842251, rs842259, rs842254 DTX4rs2211912, rs3847, rs544864 DUSP8 rs1554857, rs7396009, rs1108991,rs10734456 DYM rs577979, rs7239949, rs357894, rs16950298 EML1 rs8013843,rs12435250, rs3818279, rs4900447, rs11160554, rs1957509, rs1191109,rs11623084, rs17099031, rs10150225, rs10131519, rs1005766, rs8020741,rs2250718, rs12590861, rs975252, rs11850280, rs3783322 EVL rs1190967,rs10148930, rs2400848, rs10136836, rs12431406 EXOC2 rs12154040,rs2073008, rs1150856, rs9405242, rs2473484, rs17135931 FASLG rs10458360FUSSEL18 rs2164098, rs11877471, rs8086549, rs9304344, rs9965170,rs11082575, rs11663646, rs17785419, rs7244178 GCOM1 rs2470360,rs1873993, rs9302201, rs1425948, rs9806498, rs16977629, rs7176042,rs11638184, rs11071337 GPR135 rs1253103, rs2774052, rs4898989,rs1273156, rs1253170 GRINL1A rs2470360, rs9302201, rs11071337,rs9806498, rs7176042, rs11638184, rs1873995, rs16977629, rs1873993 HCCA2rs7396009, rs1554857, rs1108991, rs10734456 HERC2 rs8041209, rs2346050,rs6497292, rs916977, rs6497272 HSD17B12 rs7482725, rs10838166,rs10768983, rs11037691, rs10838186, rs17596617, rs10838184, rs938942,rs7116641 IGF1R rs1879613, rs4966012, rs11633717, rs1879612, rs1521481,rs7165181, rs11634874, rs4966036, rs951715, rs7173377, rs3743258 KATNAL2rs2010834, rs4986203, rs2571034, rs2576040 KCNA10 rs1281177 KCNC1rs10766426, rs2299637 KCND3 rs584096, rs1373291, rs544941, rs197412KCNH1 rs10863854, rs1777264, rs1340127, rs1777256, rs1875438, rs7529770,rs4951495, rs11119679, rs1501555, rs7546472 KCNQ1 rs2283179 KIAA0182rs1053328, rs9940601, rs732460, rs736845 KIAA0427 rs2337099, rs12458062,rs1384227, rs1023943, rs12456253, rs9952398, rs8083702, rs1994559,rs937021 KIAA0513 rs3794682, rs8063083, rs715707 KIAA1545 rs4242909KIAA1853 rs4298970, rs4767783, rs1541764, rs4075945, rs7966721,rs1568922, rs10851061, rs7298478 KLHL25 rs870689, rs17623915,rs10520595, rs11637212, rs8025135, rs2241266, rs2430838 LRRC4Crs2953310, rs10501227, rs10501225, rs1377106 N4BP1 rs8046716, rs2129243NAV2 rs10732471, rs2255677, rs2119981, rs12099330, rs2625312, rs1867116,rs11025328, rs1982265, rs1559665, rs10500860, rs7119267 NDRG2 rs1243446NDRG4 rs1058132, rs16960170, rs40359 NEDD4 rs11630780, rs4520787,rs9972348, rs12916104, rs10518831, rs1509408, rs2175104 NETO2 rs9928466OTOG rs734640, rs869108, rs11024348, rs2237959, rs972676, rs10766410,rs4757560, rs757982, rs7111528, rs11024357 PER3 rs697686, rs707463,rs228688, rs228652 PHACS rs7950395, rs3134907 PMP22 rs231020, rs230915,rs192046, rs2323653, rs10852830, rs230911, rs11656487 PTPN5 rs7117716,rs4757718, rs4075664, rs755796, rs11024782, rs7950091, rs11024786RABGAP1L rs1793319, rs10912854 RERE rs4581300, rs6577499, rs12024032,rs10779702 RHOG rs11030008, rs1869002, rs1055640 RIMBP2 rs4759462,rs1877978 RP1-21O18.1 rs761288, rs4501834, rs1000313, rs4661563,rs6665012, rs10803343 RTN1 rs1957311, rs17731838, rs1884737, rs12878097,rs17256003, rs1951366 SERGEF rs4141243, rs11024415, rs2299628,rs2283233, rs4757589 SLC16A4 rs3768458 SLC17A6 rs1562445, rs2078352,rs11026546, rs721840 SLC6A17 rs17671169, rs6689641, rs2784140, rs1571346SLC6A5 rs16906507 SLCO3A1 rs8027160, rs975721, rs12905912, rs11630872,rs207954, rs8032981 SMAD2 rs10502890, rs1792670 SMAD4 rs7243135,rs1789223 SMAD7 rs2337153, rs12953717 STX2 rs10848205, rs7956851 SV2Brs1117387, rs1002556, rs11631712, rs6496778, rs17516708, rs2269799,rs1079535, rs6496780, rs2106692, rs11630131, rs2239994 SYT13 rs7943596,rs1075778, rs1077491, rs6485608, rs7118408, rs7124508, rs12362444,rs4755941, rs7117240 SYT14 rs6701631, rs7543650, rs12029138 TEP1rs1760909, rs1713448, rs1713449, rs1713419 TOLLIP rs2672812, rs2014486TTC5 rs2318864, rs11623837, rs4981148, rs4981951, rs8022565, rs4981948ULK1 rs10794440 UNC13C rs8023723, rs500853, rs8025195, rs573320,rs12912762, rs934192, rs7163424, rs8024165, rs12917023, rs16974712,rs12900128, rs1961635, rs1864416, rs2115820, rs8024845, rs2115825,rs12148800, rs1897069, rs9920150, rs17731958 USH1C rs4756895, rs1076311,rs2237961, rs2041032, rs972676, rs1064074, rs10766410, rs2237959 VAMP4rs9943293, rs10913529 WDR25 rs11160589, rs7492607 YPEL4 rs1798173ZFP91-CNTF rs2509920, rs948562 ZNF423 rs4785185

Identification of Additional Markers by Linkage Disequilibrium Analysis

Linkage disequilibrium (LD) is a measure of the degree of associationbetween alleles in a population. One of skill in the art will appreciatethat haplotypes involving markers in LD with the polymorphisms describedherein can also be used in a similar manner to those described herein.Methods of calculating LD are known in the art (see, e.g., Morton etal., Proc Natl Acad Sci USA 98(9):5217-21 (2001); Tapper et al., ProcNatl Acad Sci USA 102(33):11835-11839 (2005); Maniatis et al., Proc NatlAcad Sci USA 99:2228-2233 (2002)).

Thus, in some embodiments, the methods include analysis of polymorphismsthat are in LD with a polymorphism described herein. Methods are knownin the art for identifying such polymorphisms; for example, theInternational HapMap Project provides a public database that can beused, see hapmap.org, as well as The International HapMap Consortium,Nature 426:789-796 (2003), and The International HapMap Consortium,Nature 437:1299-1320 (2005). Generally, it will be desirable to use aHapMap constructed using data from individuals who share ethnicity withthe subject, e.g., a HapMap for African Americans would ideally be usedto identify markers in LD with an exemplary marker described herein foruse in genotyping a subject of African American descent.

Alternatively, methods described herein can include analysis ofpolymorphisms that show a correlation coefficient (r²) of value ≧0.5with the markers described herein. Results can be obtained, e.g., fromon line public resources such as HapMap.org. The correlation coefficientis a measure of LD, and reflects the degree to which alleles at two loci(for example two SNPs) occur together, such that an allele at one SNPposition can predict the correlated allele at a second SNP position, inthe case where r² is >0.

Incorporation of Additional Haplotypes Associated with SZ,Pharmacological Response, and Psychiatric Endophenotypes

In some embodiments, the methods described herein can includedetermining the presence of a haplotype that includes one or moreadditional polymorphisms associated with SZ, pharmacological response,and psychiatric endophenotypes.

By way of example, numerous studies have implicated variousphosphatidylinositol kinases in SZ, including PIP5K2A (Bakker et al.,Genes Brain Behav. 6:113-119 (2007)) and PI3K via interaction with AKT(Kalkman, Pharmacol. Ther. 110:117-134 (2006)). The use of variants inthe PI4K2B gene in SZ diagnosis and pharmacogenomics has been described,see, e.g., International Patent Application No. PCT/US2007/078399.Additionally, insulin and diacylglycerol interact with the inositolpathways. As described herein, combining such findings withprotein-protein interaction data, pathway analyses, and the largeliterature on genetic linkage studies for neuropsychiatric illnesses,has allowed the present inventors to identify a number of inositol,insulin and diacylglycerol genes that can be used for SZ riskassessment, diagnosis and pharmacogenomics.

As a second example, potassium channels and potassium current signalingmolecules interact with many pathways including dopamine signalingpathways (Canavier et al., J. Neurophysiol. 98:3006-3022 (2007)). Thepotassium channel gene KCNIP4 has been implicated in schizophrenia risk,see, e.g., International Patent Application No. PCT/US2007/078399. Othergroups have reported the possible involvement of KCNN3 polymorphisms inSZ (Ivkovic et al., Int. J. Neurosci. 116:157-164 (2006). As describedherein, several additional potassium channel genes, as well as genesthat produce proteins that interact with potassium pathways, have beenidentified that are predicted to play a role in SZ risk and/or drugresponse.

In some embodiments, the methods described herein can includedetermining the presence of a haplotype that includes one or morepolymorphisms near D22S526 and/or the polymorphisms in the Sult4a1 geneand/or polymorphisms within 1 LDU of these markers, e.g., as describedin U.S. Pat. Pub. No. 2006-0177851, incorporated herein in its entirety.

In some embodiments, the methods described herein can includedetermining the presence of a haplotype that includes one or morepolymorphisms in the PI4K2B gene and/or polymorphisms in the KCNIP4 geneand/or polymorphisms in the CERK gene and/or polymorphisms in the SHANK3gene and/or polymorphisms within 1 LDU of these markers, e.g., asdescribed in International Pat. Application No. PCT/US2007/078399 and USPat. Pub. No. 2009-0012371, incorporated herein in its entirety.

In some embodiments, the methods described herein can includedetermining the presence of a haplotype that includes one or morepolymorphisms in the HPCAL1 gene and/or the polymorphisms in the SV2Cgene and/or polymorphisms in linkage disequilibrium with these markers,e.g., as described in International Pat. Application No.PCT/US2008/088061, incorporated herein in its entirety.

In some embodiments, the methods include determining the presence of ahaplotype that includes one or more polymorphisms in the novelSZ-spectrum genes and/or the polymorphisms in linkage disequilibriumwith specific markers in these genes, e.g., as described inPCT/US2009/030057, incorporated herein in its entirety.

Identification of Additional Markers for Use in the Methods DescribedHerein

In general, genetic markers can be identified using any of a number ofmethods well known in the art. For example, numerous polymorphisms inthe regions described herein are known to exist and are available inpublic databases, which can be searched using methods and algorithmsknown in the art. Alternately, polymorphisms can be identified bysequencing either genomic DNA or cDNA in the region in which it isdesired to find a polymorphism. According to one approach, primers aredesigned to amplify such a region, and DNA from a subject is obtainedand amplified. The DNA is sequenced, and the sequence (referred to as a“subject sequence” or “test sequence”) is compared with a referencesequence, which can represent the “normal” or “wild type” sequence, orthe “affected” sequence. In some embodiments, a reference sequence canbe from, for example, the human draft genome sequence, publiclyavailable in various databases, or a sequence deposited in a databasesuch as GenBank. In some embodiments, the reference sequence is acomposite of ethnically diverse individuals.

In general, if sequencing reveals a difference between the sequencedregion and the reference sequence, a polymorphism has been identified.The fact that a difference in nucleotide sequence is identified at aparticular site that determines that a polymorphism exists at that site.In most instances, particularly in the case of SNPs, only twopolymorphic variants will exist at any location. However, in the case ofSNPs, up to four variants may exist since there are four naturallyoccurring nucleotides in DNA. Other polymorphisms, such as insertionsand deletions, may have more than four alleles.

Other Genetic Markers of Schizophrenia

The methods described herein can also include determining the presenceor absence of other markers known or suspected to be associated with SZ,or with SD, or SPD, e.g., markers outside of a region identified herein,see, e.g., Harrison and Owen, Lancet, 361(9355):417-419 (2003),including, for example, markers on chromosome 22 and other chromosomes,e.g., in the region of 22q12.3 (e.g., near D22S283), 22q11.2, 22q11.2,22q11-q13, 1q42.1, 1q42.1, 1q21-q22, 2p, 2q, 3p25, 4p, 4q, 5q11.2-q13.3,6p22.3, 6p23, 6q13-q26, 7q, 8p12-21, 8q, 9p, 10p15-p13 (e.g., nearD105189), 10q22.3, 11q14-q21, 12q24, 13q34, 13q32, 14q32.3, 15q15, 16p,17q, 18p, 18q, 19p. 20p, 21q, Xq, and/or the X/Y pseudoautosomal region.In some embodiments, the methods include determining the presence orabsence of one or more other markers that are or may be associated withSZ, or with SZ, SD or SPD, e.g., in one or more genes, e.g., ACE (Illiet al., Eur Neuropsychopharmacol 13:147-151 (2003)); ADRA1A (Clark etal., Biol Psychiatry. 58(6):435-9 (2005)); ADH1B (Xu et al., MolPsychiatry. 9(5):510-21 (2004); Vawter et al., Hum Genet. 119(5):558-70(2006)); AHI1 (Eur J Hum Genet. 14(10):1111-9 (2006)); AKT1 (Emamian etal., Nature Genet. 36:131-137 (2004)); ALDH3B1 (Sun et al. Sci. China C.Life. Sci. 48(3):263-9 (2005)); ALK (Kunagi et al., J Neural Transm.113(10):1569-73 (2006)); APC (Cui et al., Mol Psychiatry (7):669-77(2005)); APOE (Liu et al., Schizophr Res 62: 225-230 (2003)); ARSA(Marcao et al., Mol Genet Metab. 79(4):305-7 (2003); ARVCF (Chen et al.,Schizophr Res. 72(2-3):275-7 (2005)); ATXN1 (Pujana et al Hum Genet99:772-775 (1997); Joo et al., Psychiatr Genet 9:7-11 (1999); Fallin etal., Am J Hum Genet 77:918-936 (2005)); BDNF (Neves-Pereira et al.,Molec. Psychiat. 10:208-212 (2005)); BRD1 (Severinsen et al., MolPsychiatry. 11(12):1126-38 (2006)); BZRP (Kurumaji et al., J NeuralTransm. 107(4):491-500 (2000)); DAO (Owen et al., Trends Genet.21(9):518-25 (2005)); DAOA (Owen et al., 2005, supra); CAPON(Brzustowicz et al., Am J Hum Genet. 74(5):1057-63 (2004)); CCKAR (Zhanget al., Mol Psychiatry 5:239-240 (2000); Sanjuan et al., Eur Psychiatry19:349-353 (2004)); CHGB (Kitao et al., Psychiatr Genet 10:139-143(2000); Zhang et al., Neurosci Lett 323:229-233 (2002)); CHI3L1 (Zhao etal., Am J Hum Genet. 80(1):12-8 (2007)); CHRNA2 (Blaveri et al., Europ.J. Hum. Genet. 9: 469-472 (2001)); CHRNA7 (Leonard et al. Arch GenPsychiatry. 2002 59:1085-1096 (2002); De Luca et al. Neuropsychobiology.50:124-127 (2004)); CLDN5 (Sun et al., Eur Psychiatry 19:354-357 (2004);Wei and Hemmings, Prostaglandins Leukot Essent Fatty Acids 73(6)4:41-445(2005)); COMT (Shifman et al., Am. J. Hum. Genet. 71:1296-1302 (2002));CNR1 (Ujike et al., Mol Psychiatry 7:515-518 (2002)); CPLX2 (Lee et al.,Behav Brain Funct. 1:15 (2005)); DGCR8 (Jacquet et al., Hum Mol Genet.11(19):2243-9 (2002)); DISC1 (Owen et al., 2005, supra; see, e.g., theD1S2709 marker (Ekelend et al., Hum. Molec. Genet. 10:1611-1617 (2001),DDR1 (Roig et al., Mol Psychiatry. 12(9); 833-41 (2007); DRD4 (Lung etal., Schizophr Res 57:239-245 (2002)); DDR3 (Williams et al., MolPsychiatry 3:141-149 (1998)); DRD5 (Williams et al., Psychiatr Genet7:83-85 (1997); Muir et al., Am J Med Genet 105:152-158 (2001)); HEP3haplotype, Hennah et al., Hum. Molec. Genet. 12: 3151-3159 (2003), andLeu607Pro, Hodgkinson et al., Am. J. Hum. Genet. 75:862-872 (2004),Erratum: Am. J. Hum. Genet. 76:196 (2005)); DISC2 (Millar et al., AnnMed. 36(5):367-78 (2004)); DPYSL2 (Hong et al., Am J Med Genet BNeuropsychiatr Genet. 136(1):8-11 (2005)); DRD1 (Coon et al., Am. J.Hum. Genet. 52: 327-334 (1993)); DRD2 (Glatt et al., Am. J. Psychiat.160:469-476 (2003)); DRD3 (Rybakowski et al., Molec. Psychiat. 6:718-724(2001)); DTNBP1 (Owen et al., 2005, supra); EGR3 (Yamada et al., ProcNatl Acad Sci 104(8):2815-20 (2007)); EPSIN4 (Am J Hum Genet.76(5):902-7 (2005)); ErbB; EGF (Futamura et al., Am. J. Hum. Genet. 52:327-334 (2002)); ENTH (Pimm et al., Am J Hum Genet 76:902-907 (2005);Tang et al., Mol Psychiatry 11:395-399 (2006)); ERBB4 (Norton et al., AmJ Med Genet B Neuropsychiatr Genet 14; 11; 96-101 (2005); Silberberg etal., Am J Med Genet B Neuropsychiatr Genet 141B; 2; 142-148 (2006));FEZ1 (Yamada et al., Biol Psychiatry 56:683-690 (2004)); FOXP2 (Sanjuanet al., Psychiatr Genet. 16(2):67-72 (2006)); FXYD6 (Choudhury et al.,Am J Hum Genet. 80(4):664-72 (2007)); FZD3 (Katsu et al., Neurosci Lett353:53-56 (2003); Yang et al., Biol Psychiatry 54:1298-1301 (2003);Zhang et al., Am J Med Genet 129B:16-19 (2004)); GABRA1, GABRA2, GABRA6,GABRP (Petryshen et al., Mol Psychiatry. 10(12):1057 (2005)); GABBR1(Zai et al. Eur Neuropsychopharmacol. 15:347-52 (2005); Le-Niculescu etal. Am J Med Genet B Neuropsychiatr Genet. 144:129-58 (2007)); GAD1(Addington et al., Mol Psychiatry 10:581-588 (2005)); GFRA1 (Semba etal., Brain Res Mol Brain Res. 124(1):88-95 (2004)); GCLM (Tosic et al.,Am J Hum Genet. 79(3):586-92 (2006)); GNB3 (Kunugi et al., J. NeuralTransm. 109(2):213-8 (2002)); GPR78 (Underwood et al., Mol Psychiatry.11(4):384-94 (2006)); GRIA1 (Magri et al., Am J Med Genet BNeuropsychiatr Genet 141(3):287-93 (2006)); GNPAT (Lin et al., BiolPsychiatry. 60(6):554-62 (2006)); GRID1 (Fallin et al., Am J Hum Genet77:918-936 (2005)); GRIK1 (Shibata et al., Psychiatr Genet. 11(3):139-44(2001)); GRIK2 (Shibata et al., Psychiatry Res. 113(1-2):59-67 (2002));GRIK3 (Shibata et al., Psychiatry Res. 30: 141(1): 39-51 (2006)); GRIK4(Pikard et al., Mol Psychiatry 11(9):847-57 (2006)); GRIN1 (Qin et al.,Eur J Hum Genet. 13(7):807-14 (2005)); GRIN2A, GRIN2B (Abdolmaleky etal., Am J Pharmacogenomics. 5(3):149-60 (2005)); GRIN2D (Makino et al.,Psychiatr Genet. 15(3):215-21 (2005)); GRM3 (Egan et al., Proc Natl AcadSci USA. 101(34):12604-9 (2004)); GRM4 (Ohtsuki et al., Psychiatr Genet.11(2):79-83 (2001)); GRM5 (Devon et al., Mol Psychiatry. 6(3):311-4(2001)); GSTM1 (Harada et al., Biochem Biophys Res Commun 281:267-271(2001); Pae et al., Psychiatr Genet 14:147-150 (2004)); G30/G72 (Schulzeet al., Am J Psychiatry. 162(11):2101-8 (2005)); HTR2A (Baritaki et al.,Eur J Hum Genet. 12(7):535-41 (2004)); HLA-DRB1 (Schwab et al., Am J MedGenet. 114(3):315-20 (2002)); HLA-BRB3 (Yu et al., Zhonghua Liu XingBing Xue Za Zhi. 24(9):815-8 (2003)); HTR5A (Abdolmaleky et al.,Schizophr Res 67:53-62 (2004)); HTR6 (Tsai et al., Neurosci Lett.271(2):135-7 (1999)); IL1B (Katila et al., Mol Psychiatry 4:179-181(1999); Meisenzahal et al., Am J Psychiatry 158:1316-1319 (2001);Zanardini et al., J Psychiatr Res 37:457-462 (2003)); IL1RN (Zanardiniet al., J Psychiatr Res 37:457-462 (2003); Kim et al., Psychiatr Genet14:165-167 (2004); Papiol et al., Neuroimage 27:1002-1006 (2005)); IL10(Chiavetto et al., Biol Psychiatry 51:480-484 (2002); Jun et al.,Psychiatry Clin Neurosci 56:177-180 (2002)); IL2RB (Schwab et al., Am JMed Genet. 60(5):436-43 (1995)); KCNN3 (Ujike et al., Psychiatry Res.101(3):203-7 (2001)); KIF13A (Jamain et al., Genomics. 74(1):36-44(2001)); KIF2A (Li et al., Neurosci Letters 407 (2) 151-5 (2006)); KPNA3(Wei and Hemmings, Neurosci Res. 52(4):342-6 (2005)); LGI1 (Fallin etal. A J Hum Genet. 77:918-36 (2005)); MAG (Wan et al., Neurosci Lett.388(3):126-31 (2005)); MAOA (Jonsson et al., Schizophr Res 61:31-37(2003); Wei and Hemmings. Psychiatr Genet 9, 177-181 (1999)); MED12(Sandhu et al., Am J Med Genet B Neuropsychiatr Genet. 123B: 33-38(2003); Spinks et al., Am J Med Genet B Neuropsychiatr Genet. 127B:20-27(2004)); MLC1 (Verma et al., Biol Psychiatry. 58(1):16-22 (2005)); MTHFR(Lewis et al., Am. J. Med. Genet. (Neuropsychiat. Genet.) 135B:2-4(2005)); MTR (Kempisty et al., Psychiatr Genet. 17(3):177-81 (2007));MTHFD1 (Kempisty et al., Psychiatr Genet. 17(3):177-81 (2007)); NCAM1(Sullivan et al., Biol Psychiatry. 61(7):902-10 (2007)); NDE1 (Hennah etal., Hum Mol Genet. 16(5):453-62 (2006)); NDUFV2 (Waskizuka et al., Am JMed Genet B Neuropsychiatr Genet. 141(3):301-4 (2006)); NOS1 (Liou etal., Schizophr Res. 65(1):57-9 (2003)); NOTCH4 (Wei and Hemmings,(Letter) Nature Genet. 25:376-377 (2000)); NPAS3 (Kamnasaran et al., JMed Genet 40:325-332 (2003)); NRG1 (Owen et al., 2005, supra); NRG3(Fallin et al. A J Hum Genet. 77:918-36 (2005)); NTNG1 (Fukawasa et al.,J Med Dent Sci 51:121-128 (2004); Aoki-Suzuki et al., Biol Psychiatry57:382-393 (2005)); NTNG2 (Aoki-Suzuki et al., Biol Psychiatry57:382-393 (2005)); NTF3 (Jonsson et al., Acta Psychiatr Scand95:414-419 (1997)); OLIG2 (Georgieva et al., Proc Natl Acad Sci103(33):12469-74 (2006)); PCQAP (Sandhu et al., Psychiatr Genet.14(3):169-72 (2004)); PDE4B (Millar et al., Science 310:1187-1191(2005)); PDLIM5 (Horiuchi et al., Biol Psychiatry 59(5):434-9 (2005));PICK1 (Hong et al., Neuroreport 15:1965-1967 (2004); Fujii et al.,Molecular Psychiatry 11:150-157 (2005)); PIK3C3 (Stopkova et al., BiolPsychiatry 55:981-988 (2004); Duan et al., Neurosci Lett., 379:32-36(2005)); PIK4CA (Saito et al., Am J Med Genet B Neuropsychiatr Genet.116(1):77-83 (2003)); PIP5K2A (Stopkova et al., Psychiatr Genet. 15(3):223-7 (2005)); PLA2G4A, PLA2G4C (Yu et al., Prostaglandins Leukot EssentFatty Acids. 73(5):351-4 (2005)); PLA2G4B (Tao et al., Am J Med Genet BNeuropsychiatr Genet 137:56-58 (2005)); PLXNA2 (Mah et al., MolecularPsychiatry 11:471-478 (2006)); PTGS2 (Wei and Hemmings. ProstaglandinsLeukot Essent Fatty Acids 70:413-415 (2004)); PPP3CC (Gerber et al.,Proc Natl Acad Sci USA. 100(15):8993-8 (2003)); PNOC (Blaveri et al.,2001); PRODH (Chakravarti, Proc. Nat. Acad. Sci. 99:4755-4756 (2002));QKI (Aberg et al., Am J Med Genet B Neuropsychiatr Genet. 2005 Dec. 9;[Epub ahead of print]); RGS4 (Chowdari et al., Hum. Molec. Genet.11:1373-1380 (2002), Erratum: Hum. Molec. Genet. 12:1781 (2003)); RELN(Costa et al., Mol Interv. 2(1):47-57 (2002)); RTN4 (Novak et al., BrainRes Mol Brain Res 107:183-189 (2002); Tan et al., Brain Res Mol BrainRes 139:212-216 (2005)); SCA1 (Culkjovic et al., Am J Med Genet.96(6):884-7 (2000)); SLC15A1 (Maheshwari et al., BMC Genomics. 3(1):30(2002)); SLC18A1 (Bly, Schizophr Res. 78(2-3):337-8 (2005)); SLC18A2(Gutierrez et al. Am J Med Genet B Neuropsychiatr Genet. 144(4):502-7(2007)); SLC6A4 (Fan and Sklar, Mol Psychiatry. 10(10):928-38, 891(2005)); SNAP29 (Saito et al., Mol Psychiatry 6(2):193-201 (2001);Erratum in: Mol Psychiatry 6(5):605 (2001); SULT4A1 (Brennan andChondra. Am J Med Genet B Neuropsychiatr Genet. 139(1):69-72 (2005));SYNGR1 (Verma et al., Biol Psychiatry. 55(2):196-9 (2004)); SYN2 (Chenet al., Bio. Psychiat. 56:177-181 (2004)); SYN3 (Porton et al. BiolPsychiatry. 55(2):118-25 (2004)); TAAR4 (Duan et al., Am J Hum Genet75:624-638 (2004)); TBP/SCA17 (Chen et al., Schizophr Res. 78(2-3):131-6(2005)); TH (Kurumaji et al., J Neural Transm 108:489-495 (2001); Meloniet al., C R Acad Sci III 318:803-809 (1995)); TNFA (Morar et al., Am JMed Genet B Neuropsychiatr Genet. 144(3):318-24 (2007)); TPH1 (Nolan etal., Psychiatr Genet 10:109-115 (2000); Hong et al., Schizophr Res49:59-63 (2001); Sekizawa et al., Am J Med Genet B Neuropsychiatr Genet128:24-26 (2004)); TPP2 (Fallin et al. A J Hum Genet. 77:918-36 (2005));TPS3 (Park et al., Schizophr Res 67:71-74 (2004); Ni et al., NeurosciLett 388:173-178 (2005)); TRAR4 (Am J Hum Genet. 75(4):624-38 (2004));TRAX (Thomson et al., Mol Psychiatry. 10(7):657-68, 616 (2005)); UFD1L(De Luca et al., Am J Med Genet. 105(6):529-33 (2001)); UCP2 (Yasuno etal., Am J Med Genet B Neuropsychiatr Genet. 144(2):250-3 (2007)); UCP4(Yasuno et al., Am J Med Genet B Neuropsychiatr Genet. 144(2):250-3(2007)); UHMK1 (Puri et al., Biol Psychiatry 61(7):873-9 (2007)); XBP1(Chen et al., Biochem Biophys Res Commun 319:866-870 (2004); Kakiuchi etal., Psychiatry Clin Neurosci 58:438-440 (2004)); YWHAH (Toyooka et al.,Am J Med Genet. 88(2):164-7 (1999)); ZDHHC8 (Mukai et al., Nature Genet.36:725-731 (2004)); or ZNF74 (Takase et al., Schizophr Res. 52(3):161-5(2001)). See also, e.g., OMIM entry no. 181500 (SCZD).

Methods of Determining the Presence or Absence of a Haplotype Associatedwith SZ, Pharmacological Response, and Psychiatric Endophenotypes

The methods described herein include determining the presence or absenceof haplotypes associated with SZ, pharmacological response, andpsychiatric endophenotypes. In some embodiments, an association with SZis determined by the presence of a shared haplotype between the subjectand an affected reference individual, e.g., a first or second-degreerelation of the subject, or population of affected individuals, and theabsence of the haplotype in an unaffected reference individual. In someembodiments, an association with a pharmacological response isdetermined by the presence of a shared haplotype between the subject anda reference individual (or population) who had an identified response toa pharmacological treatment. In some embodiments, an association with aspecific psychiatric endophenotype is determined by the presence of ashared haplotype between the subject and a reference subject orpopulation with (or without) the specific endophenotype. Thus themethods can also include obtaining and analyzing a sample from asuitable reference individual.

Samples that are suitable for use in the methods described hereincontain genetic material, e.g., genomic DNA (gDNA). Non-limitingexamples of sources of samples include urine, blood, and tissue. Thesample itself will typically consist of nucleated cells (e.g., blood orbuccal cells), tissue, etc., removed from the subject. The subject canbe an adult, child, fetus, or embryo. In some embodiments, the sample isobtained prenatally, either from a fetus or embryo or from the mother(e.g., from fetal or embryonic cells in the maternal circulation).Methods and reagents are known in the art for obtaining, processing, andanalyzing samples. In some embodiments, the sample is obtained with theassistance of a health care provider, e.g., to draw blood. In someembodiments, the sample is obtained without the assistance of a healthcare provider, e.g., where the sample is obtained non-invasively, suchas a sample comprising buccal cells that is obtained using a buccal swabor brush, or a mouthwash sample.

The sample may be further processed before the detecting step. Forexample, DNA in a cell or tissue sample can be separated from othercomponents of the sample. The sample can be concentrated and/or purifiedto isolate DNA. Cells can be harvested from a biological sample usingstandard techniques known in the art. For example, cells can beharvested by centrifuging a cell sample and resuspending the pelletedcells. The cells can be resuspended in a buffered solution such asphosphate-buffered saline (PBS). After centrifuging the cell suspensionto obtain a cell pellet, the cells can be lysed to extract DNA, e.g.,gDNA. See, e.g., Ausubel et al., 2003, supra. All samples obtained froma subject, including those subjected to any sort of further processing,are considered to be obtained from the subject.

The absence or presence of a haplotype associated with SZ,pharmacological response, and/or psychiatric endophenotypes, asdescribed herein can be determined using methods known in the art, e.g.,gel electrophoresis, capillary electrophoresis, size exclusionchromatography, sequencing, and/or arrays to detect the presence orabsence of the marker(s) of the haplotype. Amplification of nucleicacids, where desirable, can be accomplished using methods known in theart, e.g., PCR.

Methods of nucleic acid analysis to detect polymorphisms and/orpolymorphic variants include, e.g., microarray analysis. Hybridizationmethods, such as Southern analysis, Northern analysis, or in situhybridizations, can also be used (see Current Protocols in MolecularBiology, Ausubel, F. et al., eds., John Wiley & Sons 2003). To detectmicrodeletions, fluorescence in situ hybridization (FISH) using DNAprobes that are directed to a putatively deleted region in a chromosomecan be used. For example, probes that detect all or a part of amicrosatellite marker can be used to detect microdeletions in the regionthat contains that marker.

Other methods include direct manual sequencing (Church and Gilbert,Proc. Natl. Acad. Sci. USA 81:1991-1995 (1988); Sanger et al., Proc.Natl. Acad. Sci. 74:5463-5467 (1977); Beavis et al. U.S. Pat. No.5,288,644); automated fluorescent sequencing; single-strandedconformation polymorphism assays (SSCP); clamped denaturing gelelectrophoresis (CDGE); two-dimensional gel electrophoresis (2DGE orTDGE); conformational sensitive gel electrophoresis (CSGE); denaturinggradient gel electrophoresis (DGGE) (Sheffield et al., Proc. Natl. Acad.Sci. USA 86:232-236 (1989)), mobility shift analysis (Orita et al.,Proc. Natl. Acad. Sci. USA 86:2766-2770 (1989)), restriction enzymeanalysis (Flavell et al., Cell 15:25 (1978); Geever et al., Proc. Natl.Acad. Sci. USA 78:5081 (1981)); quantitative real-time PCR (Raca et al.,Genet Test 8(4):387-94 (2004)); heteroduplex analysis; chemical mismatchcleavage (CMC) (Cotton et al., Proc. Natl. Acad. Sci. USA 85:4397-4401(1985)); RNase protection assays (Myers et al., Science 230:1242(1985)); use of polypeptides that recognize nucleotide mismatches, e.g.,E. coli mutS protein; allele-specific PCR, for example. See, e.g., U.S.Patent Publication No. 2004/0014095, to Gerber et al., which isincorporated herein by reference in its entirety. In some embodiments,the methods described herein include determining the sequence of theentire region of the genes listed in Tables A and B e.g. between andincluding the delimiting SNPs for the particular gene. In someembodiments, the sequence is determined on both strands of DNA.

In order to detect polymorphisms and/or polymorphic variants, it willfrequently be desirable to amplify a portion of genomic DNA (gDNA)encompassing the polymorphic site. Such regions can be amplified andisolated by PCR using oligonucleotide primers designed based on genomicand/or cDNA sequences that flank the site. See e.g., PCR Primer: ALaboratory Manual, Dieffenbach and Dveksler, (Eds.); McPherson et al.,PCR Basics: From Background to Bench (Springer Verlag, 2000); Manila etal., Nucleic Acids Res., 19:4967 (1991); Eckert et al., PCR Methods andApplications, 1:17 (1991); PCR (eds. McPherson et al., IRL Press,Oxford); and U.S. Pat. No. 4,683,202. Other amplification methods thatmay be employed include the ligase chain reaction (LCR) (Wu and Wallace,Genomics, 4:560 (1989), Landegren et al., Science, 241:1077 (1988),transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA,86:1173 (1989)), self-sustained sequence replication (Guatelli et al.,Proc. Nat. Acad. Sci. USA, 87:1874 (1990)), and nucleic acid basedsequence amplification (NASBA). Guidelines for selecting primers for PCRamplification are well known in the art. See, e.g., McPherson et al.,PCR Basics: From Background to Bench, Springer-Verlag, 2000. A varietyof computer programs for designing primers are available, e.g., ‘Oligo’(National Biosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), andthe GCG suite of sequence analysis programs (Genetics Computer Group,Madison, Wis. 53711).

In one example, a sample (e.g., a sample comprising genomic DNA), isobtained from a subject. The DNA in the sample is then examined todetermine a haplotype as described herein. The haplotype can bedetermined by any method described herein, e.g., by sequencing or byhybridization of the gene in the genomic DNA, RNA, or cDNA to a nucleicacid probe, e.g., a DNA probe (which includes cDNA and oligonucleotideprobes) or an RNA probe. The nucleic acid probe can be designed tospecifically or preferentially hybridize with a particular polymorphicvariant.

In some embodiments, a peptide nucleic acid (PNA) probe can be usedinstead of a nucleic acid probe in the hybridization methods describedabove. PNA is a DNA mimetic with a peptide-like, inorganic backbone,e.g., N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T orU) attached to the glycine nitrogen via a methylene carbonyl linker(see, e.g., Nielsen et al., Bioconjugate Chemistry, The AmericanChemical Society, 5:1 (1994)). The PNA probe can be designed tospecifically hybridize to a nucleic acid comprising a polymorphicvariant conferring susceptibility to or indicative of the presence ofSZ.

In some embodiments, restriction digest analysis can be used to detectthe existence of a polymorphic variant of a polymorphism, if alternatepolymorphic variants of the polymorphism result in the creation orelimination of a restriction site. A sample containing genomic DNA isobtained from the individual. Polymerase chain reaction (PCR) can beused to amplify a region comprising the polymorphic site, andrestriction fragment length polymorphism analysis is conducted (seeAusubel et al., Current Protocols in Molecular Biology, supra). Thedigestion pattern of the relevant DNA fragment indicates the presence orabsence of a particular polymorphic variant of the polymorphism and istherefore indicative of the presence or absence of susceptibility to SZ.

Sequence analysis can also be used to detect specific polymorphicvariants. A sample comprising DNA or RNA is obtained from the subject.PCR or other appropriate methods can be used to amplify a portionencompassing the polymorphic site, if desired. The sequence is thenascertained, using any standard method, and the presence of apolymorphic variant is determined.

Allele-specific oligonucleotides can also be used to detect the presenceof a polymorphic variant, e.g., through the use of dot-blothybridization of amplified oligonucleotides with allele-specificoligonucleotide (ASO) probes (see, for example, Saiki et al., Nature(London) 324:163-166 (1986)). An “allele-specific oligonucleotide” (alsoreferred to herein as an “allele-specific oligonucleotide probe”) istypically an oligonucleotide of approximately 10-50 base pairs,preferably approximately 15-30 base pairs, that specifically hybridizesto a nucleic acid region that contains a polymorphism. Anallele-specific oligonucleotide probe that is specific for particular apolymorphism can be prepared using standard methods (see Ausubel et al.,Current Protocols in Molecular Biology, supra).

Generally, to determine which of multiple polymorphic variants ispresent in a subject, a sample comprising DNA is obtained from theindividual. PCR can be used to amplify a portion encompassing thepolymorphic site. DNA containing the amplified portion may bedot-blotted, using standard methods (see Ausubel et al., CurrentProtocols in Molecular Biology, supra), and the blot contacted with theoligonucleotide probe. The presence of specific hybridization of theprobe to the DNA is then detected. Specific hybridization of anallele-specific oligonucleotide probe (specific for a polymorphicvariant indicative of susceptibility to SZ) to DNA from the subject isindicative of susceptibility to SZ.

In some embodiments, fluorescence polarization template-directeddye-terminator incorporation (FP-TDI) is used to determine which ofmultiple polymorphic variants of a polymorphism is present in a subject(Chen et al., (1999) Genome Research, 9(5):492-498). Rather thaninvolving use of allele-specific probes or primers, this method employsprimers that terminate adjacent to a polymorphic site, so that extensionof the primer by a single nucleotide results in incorporation of anucleotide complementary to the polymorphic variant at the polymorphicsite.

Real-time pyrophosphate DNA sequencing is yet another approach todetection of polymorphisms and polymorphic variants (Alderborn et al.,(2000) Genome Research, 10(8):1249-1258). Additional methods include,for example, PCR amplification in combination with denaturing highperformance liquid chromatography (dHPLC) (Underhill, P. A., et al.,Genome Research, Vol. 7, No. 10, pp. 996-1005, 1997).

The methods can include determining the genotype of a subject withrespect to both copies of the polymorphic site present in the genome.For example, the complete genotype may be characterized as −/−, as −/+,or as +/+, where a minus sign indicates the presence of the reference orwild type sequence at the polymorphic site, and the plus sign indicatesthe presence of a polymorphic variant other than the reference sequence.If multiple polymorphic variants exist at a site, this can beappropriately indicated by specifying which ones are present in thesubject. Any of the detection means described herein can be used todetermine the genotype of a subject with respect to one or both copiesof the polymorphism present in the subject's genome.

In some embodiments, it is desirable to employ methods that can detectthe presence of multiple polymorphisms (e.g., polymorphic variants at aplurality of polymorphic sites) in parallel or substantiallysimultaneously. Oligonucleotide arrays represent one suitable means fordoing so. Other methods, including methods in which reactions (e.g.,amplification, hybridization) are performed in individual vessels, e.g.,within individual wells of a multi-well plate or other vessel may alsobe performed so as to detect the presence of multiple polymorphicvariants (e.g., polymorphic variants at a plurality of polymorphicsites) in parallel or substantially simultaneously according to certainembodiments of the invention.

Probes

Nucleic acid probes can be used to detect and/or quantify the presenceof a particular target nucleic acid sequence within a sample of nucleicacid sequences, e.g., as hybridization probes, or to amplify aparticular target sequence within a sample, e.g., as a primer. Probeshave a complimentary nucleic acid sequence that selectively hybridizesto the target nucleic acid sequence. In order for a probe to hybridizeto a target sequence, the hybridization probe must have sufficientidentity with the target sequence, i.e., at least 70%, e.g., 80%, 90%,95%, 98% or more identity to the target sequence. The probe sequencemust also be sufficiently long so that the probe exhibits selectivityfor the target sequence over non-target sequences. For example, theprobe will be at least 20, e.g., 25, 30, 35, 50, 100, 200, 300, 400,500, 600, 700, 800, 900 or more, nucleotides in length. In someembodiments, the probes are not more than 30, 50, 100, 200, 300, 500,750, or 1000 nucleotides in length. Probes are typically about 20 toabout 1×10⁶ nucleotides in length. Probes include primers, whichgenerally refers to a single-stranded oligonucleotide probe that can actas a point of initiation of template-directed DNA synthesis usingmethods such as PCR (polymerase chain reaction), LCR (ligase chainreaction), etc., for amplification of a target sequence.

In some embodiments, the probe is a test probe, e.g., a probe that canbe used to detect polymorphisms in a region described herein, e.g.,polymorphisms as described herein. In some embodiments, the probe canhybridize to a target sequence within a region delimited by delimitingSNPs, SNP1 and SNP2, inclusive as specified for the particular genes inTables A and B.

In some embodiments, the probe can bind to another marker sequenceassociated with SZ as described herein.

Control probes can also be used. For example, a probe that binds a lessvariable sequence, e.g., repetitive DNA associated with a centromere ofa chromosome, can be used as a control. Probes that hybridize withvarious centromeric DNA and locus-specific DNA are availablecommercially, for example, from Vysis, Inc. (Downers Grove, Ill.),Molecular Probes, Inc. (Eugene, Oreg.), or from Cytocell (Oxfordshire,UK). Probe sets are available commercially, e.g., from AppliedBiosystems, e.g., the Assays-on-Demand SNP kits Alternatively, probescan be synthesized, e.g., chemically or in vitro, or made fromchromosomal or genomic DNA through standard techniques. For example,sources of DNA that can be used include genomic DNA, cloned DNAsequences, somatic cell hybrids that contain one, or a part of one,human chromosome along with the normal chromosome complement of thehost, and chromosomes purified by flow cytometry or microdissection. Theregion of interest can be isolated through cloning, or by site-specificamplification via the polymerase chain reaction (PCR). See, for example,Nath and Johnson, Biotechnic. Histochem., 1998, 73(1):6-22, Wheeless etal., Cytometry 1994, 17:319-326, and U.S. Pat. No. 5,491,224.

In some embodiments, the probes are labeled, e.g., by direct labeling,with a fluorophore, an organic molecule that fluoresces after absorbinglight of lower wavelength/higher energy. A directly labeled fluorophoreallows the probe to be visualized without a secondary detectionmolecule. After covalently attaching a fluorophore to a nucleotide, thenucleotide can be directly incorporated into the probe with standardtechniques such as nick translation, random priming, and PCR labeling.Alternatively, deoxycytidine nucleotides within the probe can betransaminated with a linker. The fluorophore then is covalently attachedto the transaminated deoxycytidine nucleotides. See, e.g., U.S. Pat. No.5,491,224.

Fluorophores of different colors can be chosen such that each probe in aset can be distinctly visualized. For example, a combination of thefollowing fluorophores can be used: 7-amino-4-methylcoumarin-3-aceticacid (AMCA), Texas Red™ (Molecular Probes, Inc., Eugene, Oreg.), 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate (FITC),7-diethylaminocoumarin-3-carboxylic acid, tetramethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)-carboxytetramethylrhodamine,7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5-(and-6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4adiaza-3-indacenepropionic acid, eosin-5-isothiocyanate,erythrosin-5-isothiocyanate, and Cascade™ blue acetylazide (MolecularProbes, Inc., Eugene, Oreg.). Fluorescently labeled probes can be viewedwith a fluorescence microscope and an appropriate filter for eachfluorophore, or by using dual or triple band-pass filter sets to observemultiple fluorophores. See, for example, U.S. Pat. No. 5,776,688.Alternatively, techniques such as flow cytometry can be used to examinethe hybridization pattern of the probes. Fluorescence-based arrays arealso known in the art.

In other embodiments, the probes can be indirectly labeled with, e.g.,biotin or digoxygenin, or labeled with radioactive isotopes such as ³²Pand ³H. For example, a probe indirectly labeled with biotin can bedetected by avidin conjugated to a detectable marker. For example,avidin can be conjugated to an enzymatic marker such as alkalinephosphatase or horseradish peroxidase. Enzymatic markers can be detectedin standard colorimetric reactions using a substrate and/or a catalystfor the enzyme. Catalysts for alkaline phosphatase include5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium.Diaminobenzoate can be used as a catalyst for horseradish peroxidase.

Oligonucleotide probes that exhibit differential or selective binding topolymorphic sites may readily be designed by one of ordinary skill inthe art. For example, an oligonucleotide that is perfectly complementaryto a sequence that encompasses a polymorphic site (i.e., a sequence thatincludes the polymorphic site, within it or at one end) will generallyhybridize preferentially to a nucleic acid comprising that sequence, asopposed to a nucleic acid comprising an alternate polymorphic variant.

Arrays and Uses Thereof

In another aspect, the invention features arrays that include asubstrate having a plurality of addressable areas, and methods of usingthem. At least one area of the plurality includes a nucleic acid probethat binds specifically to a sequence comprising a polymorphism listedin Table B, and can be used to detect the absence or presence of saidpolymorphism, e.g., one or more SNPs, microsatellites, minisatellites,or indels, as described herein, to determine a haplotype. For example,the array can include one or more nucleic acid probes that can be usedto detect a polymorphism listed in Table B. In some embodiments, thearray further includes at least one area that includes a nucleic acidprobe that can be used to specifically detect another marker associatedwith SZ as described herein. The substrate can be, e.g., atwo-dimensional substrate known in the art such as a glass slide, awafer (e.g., silica or plastic), a mass spectroscopy plate, or athree-dimensional substrate such as a gel pad. In some embodiments, theprobes are nucleic acid capture probes.

Methods for generating arrays are known in the art and include, e.g.,photolithographic methods (see, e.g., U.S. Pat. Nos. 5,143,854;5,510,270; and 5,527,681), mechanical methods (e.g., directed-flowmethods as described in U.S. Pat. No. 5,384,261), pin-based methods(e.g., as described in U.S. Pat. No. 5,288,514), and bead-basedtechniques (e.g., as described in PCT US/93/04145). The array typicallyincludes oligonucleotide probes capable of specifically hybridizing todifferent polymorphic variants. According to the method, a nucleic acidof interest, e.g., a nucleic acid encompassing a polymorphic site,(which is typically amplified) is hybridized with the array and scanned.Hybridization and scanning are generally carried out according tostandard methods. See, e.g., Published PCT Application Nos. WO 92/10092and WO 95/11995, and U.S. Pat. No. 5,424,186. After hybridization andwashing, the array is scanned to determine the position on the array towhich the nucleic acid hybridizes. The hybridization data obtained fromthe scan is typically in the form of fluorescence intensities as afunction of location on the array.

Arrays can include multiple detection blocks (i.e., multiple groups ofprobes designed for detection of particular polymorphisms). Such arrayscan be used to analyze multiple different polymorphisms. Detectionblocks may be grouped within a single array or in multiple, separatearrays so that varying conditions (e.g., conditions optimized forparticular polymorphisms) may be used during the hybridization. Forexample, it may be desirable to provide for the detection of thosepolymorphisms that fall within G-C rich stretches of a genomic sequence,separately from those falling in A-T rich segments.

Additional description of use of oligonucleotide arrays for detection ofpolymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and5,837,832. In addition to oligonucleotide arrays, cDNA arrays may beused similarly in certain embodiments of the invention.

The methods described herein can include providing an array as describedherein; contacting the array with a sample, e.g., a portion of genomicDNA that includes at least a portion of human chromosome 1, 3, 6, 10,11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, e.g., a region betweendelimiting SNPs, SNP1 and SNP2 for each of the genes listed in Tables Aand B, and/or optionally, a different portion of genomic DNA, e.g., aportion that includes a different portion of human chromosomes 1, 3, 6,10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, or anotherchromosome, e.g., including another region associated with SZ,pharmacological response, and/or psychiatric endophenotypes, anddetecting binding of a nucleic acid from the sample to the array.Optionally, the method includes amplifying nucleic acid from the sample,e.g., genomic DNA that includes a portion of a human chromosomedescribed herein, and, optionally, a region that includes another regionassociated with SZ, pharmacological response, and/or psychiatricendophenotypes, prior to or during contact with the array.

In some aspects, the methods described herein can include using an arraythat can ascertain differential expression patterns or copy numbers ofone or more genes in samples from normal and affected individuals (see,e.g., Redon et al., Nature. 444(7118):444-54 (2006)). For example,arrays of probes to a marker described herein can be used to measurepolymorphisms between DNA from a subject having SZ and control DNA,e.g., DNA obtained from an individual that does not have SZ and has nofamilial risk factors for SZ. Since the clones on the array containsequence tags, their positions on the array are accurately knownrelative to the genomic sequence. Different hybridization patternsbetween DNA from an individual afflicted with SZ and DNA from a normalindividual at areas in the array corresponding to markers in humanchromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20 asdescribed herein, and, optionally, one or more other regions associatedwith SZ, SD, or SPD, are indicative of a risk of SZ-spectrum disorders.Methods for array production, hybridization, and analysis are described,e.g., in Snijders et al., (2001) Nat. Genetics 29:263-264; Klein et al.,(1999) Proc. Natl Acad. Sci. U.S.A. 96:4494-4499; Albertson et al.,(2003) Breast Cancer Research and Treatment 78:289-298; and Snijders etal. “BAC microarray based comparative genomic hybridization.” In: Zhaoet al. (eds), Bacterial Artificial Chromosomes: Methods and Protocols,Methods in Molecular Biology, Humana Press, 2002. Real time quantitativePCR can also be used to determine copy number.

In another aspect, the invention features methods of determining theabsence or presence of a haplotype associated with SZ, pharmacologicalresponse, and/or psychiatric endophenotypes, as described herein, usingan array described above. For example, in some embodiments the methodsinclude providing a two dimensional array having a plurality ofaddresses, each address of the plurality being positionallydistinguishable from each other address of the plurality having a uniquenucleic acid capture probe, contacting the array with a first samplefrom a test subject who is suspected of having or being at risk for SZ,and comparing the binding of the first sample with one or morereferences, e.g., binding of a sample from a subject who is known tohave SZ and/or binding of a sample from a subject who is unaffected,e.g., a control sample from a subject that does not have SZ. In someembodiments, the methods include contacting the array with a secondsample from a subject who has SZ; and comparing the binding of the firstsample with the binding of the second sample. In some embodiments, themethods include contacting the array with a third sample from a subjectthat does not have SZ; and comparing the binding of the first samplewith the binding of the third sample. In some embodiments, the secondand third samples are from first or second-degree relatives of the testsubject. Binding, e.g., in the case of a nucleic acid hybridization,with a capture probe at an address of the plurality, can be detected byany method known in the art, e.g., by detection of a signal generatedfrom a label attached to the nucleic acid.

Schizophrenia, Schizotypal Personality Disorder, and SchizoaffectiveDisorder

The methods described herein can be used to determine an individual'srisk of developing schizophrenia (SZ), which as defined herein includesnarrowly defined SZ as well as schizotypal personality disorder (SPD),and/or schizoaffective disorder (SD).

Schizophrenia (SZ)

SZ is considered a clinical syndrome, and is probably a constellation ofseveral pathologies. Substantial heterogeneity is seen between cases;this is thought to reflect multiple overlapping etiologic factors,including both genetic and environmental contributions. A diagnosis ofSZ is typically indicated by chronic psychotic symptoms, e.g.,hallucinations and delusions. Disorganization of thought and behaviorare common and are considered distinguishing factors in the diagnosis ofSZ. Patients typically have some subtle impairments in cognition.Reduced emotional experience and expression, low drive, and impairedspeech are observed in a subgroup of patients. Cognitive, emotional andsocial impairments often appear early in life, while the psychoticsymptoms typically manifest in late adolescence or early adulthood inmen, a little later in women.

A diagnosis of SZ can be made according to the criteria reported in theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision, American Psychiatric Association, 2000, (referred toherein as DSM-IV) as follows:

Diagnostic Criteria for SZ

All six criteria must be met for a diagnosis of SZ.

A. Characteristic symptoms: Two (or more) of the following, each presentfor a significant portion of time during a one month period (or less ifsuccessfully treated):

(1) delusions

(2) hallucinations

(3) disorganized speech (e.g., frequent derailment or incoherence)

(4) grossly disorganized or catatonic behavior

(5) negative symptoms, e.g., affective flattening, alogia, or avolition

Only one criterion A symptom is required if delusions are bizarre orhallucinations consist of a voice keeping up a running commentary on theperson's behavior or thoughts, or two or more voices conversing witheach other.

B. Social/occupational dysfunction: For a significant portion of thetime since the onset of the disturbance, one or more major areas offunctioning such as work, interpersonal relations, or self-care aremarkedly below the level achieved prior to the onset (or when the onsetis in childhood or adolescence, failure to achieve expected level ofinterpersonal, academic, or occupational achievement).

C. Duration: Continuous signs of the disturbance persist for at least 6months. This 6-month period must include at least 1 month of symptoms(or less if successfully treated) that meet Criterion A (i.e.,active-phase symptoms) and may include periods of prodromal or residualsymptoms. During these prodromal or residual periods, the signs of thedisturbance may be manifested by only negative symptoms or two or moresymptoms listed in Criterion A present in an attenuated form (e.g., oddbeliefs, unusual perceptual experiences).

D. Schizoaffective and Mood Disorder Exclusion: Schizoaffective Disorderand Mood Disorder With Psychotic Features have been ruled out becauseeither (1) no major depressive, manic, or mixed episodes have occurredconcurrently with the active-phase symptoms; or (2) if mood episodeshave occurred during active-phase symptoms, their total duration hasbeen brief relative to the duration of the active and residual periods.

E. Substance/General Medical Condition Exclusion: The disturbance is notdue to the direct physiological effects of a substance (e.g., a drug ofabuse, a medication) or a general medical condition.

F. Relationship to a Pervasive Developmental Disorder: If the patienthas a history of Autistic Disorder or another Pervasive DevelopmentalDisorder, the additional diagnosis of SZ is made only if prominentdelusions or hallucinations are also present for at least a month (orless if successfully treated).

Schizoaffective Disorder (SD)

SD is characterized by the presence of affective (depressive or manic)symptoms and schizophrenic symptoms within the same, uninterruptedepisode of illness.

Diagnostic Criteria for Schizoaffective Disorder

The DSM-IV Criteria for a diagnosis of schizoaffective disorder is asfollows:

An uninterrupted period of illness during which, at some time, there iseither (1) a Major Depressive Episode (which must include depressedmood), (2) a Manic Episode, or (3) a Mixed Episode, concurrent withsymptoms that meet (4) Criterion A for SZ, above.

A. Criteria for Major Depressive Episode

At least five of the following symptoms must be present during the same2-week period and represent a change from previous functioning; at leastone of the symptoms is either (1) depressed mood or (2) loss of interestor pleasure.

(1) depressed mood most of the day, nearly every day, as indicated byeither subjective report (e.g., feels sad or empty) or observation madeby others (e.g., appears tearful). In children and adolescents, this canbe an irritable mood.

(2) markedly diminished interest or pleasure in all, or almost all,activities most of the day, nearly every day (as indicated by eithersubjective account or observation made by others)

(3) significant weight loss when not dieting or weight gain (e.g., achange of more than 5% of body weight in a month), or decrease orincrease in appetite nearly every day. (In children, failure to makeexpected weight gains is considered).

(4) insomnia or hypersomnia nearly every day

(5) psychomotor agitation or retardation nearly every day (observable byothers, not merely subjective feelings of restlessness or being sloweddown)

(6) fatigue or loss of energy nearly every day

(7) feelings of worthlessness or excessive or inappropriate guilt (whichmay be delusional) nearly every day (not merely self-reproach or guiltabout being sick)

(8) diminished ability to think or concentrate, or indecisiveness,nearly every day (either by subjective account or as observed by others)

(9) recurrent thoughts of death (not just fear of dying), recurrentsuicidal ideation without a specific plan, or a suicide attempt or aspecific plan for committing suicide

In addition, the symptoms do not meet criteria for a Mixed Episode. Thesymptoms cause clinically significant distress or impairment in social,occupational, or other important areas of functioning. The symptoms arenot due to the direct physiological effects of a substance (e.g., a drugof abuse, a medication) or a general medical condition (e.g.,hypothyroidism).

The symptoms are not better accounted for by Bereavement, i.e., afterthe loss of a loved one, the symptoms persist for longer than 2 months,or are characterized by marked functional impairment, morbidpreoccupation with worthlessness, suicidal ideation, psychotic symptoms,or psychomotor retardation.

B. Criteria for Manic Episode

A manic episode is a distinct period of abnormally and persistentlyelevated, expansive, or irritable mood, lasting at least one week (orany duration, if hospitalization is necessary).

During the period of mood disturbance, three (or more) of the followingsymptoms have persisted (four if the mood is only irritable) and havebeen present to a significant degree:

(1) inflated self-esteem or grandiosity

(2) decreased need for sleep (e.g., feels rested after only 3 hours ofsleep)

(3) more talkative than usual or pressure to keep talking

(4) flight of ideas or subjective experience that thoughts are racing

(5) distractibility (i.e., attention too easily drawn to unimportant orirrelevant external stimuli)

(6) increase in goal-directed activity (either socially, at work orschool, or sexually) or psychomotor agitation

(7) excessive involvement in pleasurable activities that have a highpotential for painful consequences (e.g., engaging in unrestrainedbuying sprees, sexual indiscretions, or foolish business investments)

The symptoms do not meet criteria for a Mixed Episode. The mooddisturbance is sufficiently severe to cause marked impairment inoccupational functioning or in usual social activities or relationshipswith others, or to necessitate hospitalization to prevent harm to selfor others, or there are psychotic features. The symptoms are not due tothe direct physiological effects of a substance (e.g., a drug of abuse,a medication, or other treatment) or a general medical condition (e.g.,hyperthyroidism).

C. Criteria for Mixed Episode

A mixed episode occurs when the criteria are met both for a ManicEpisode and for a Major Depressive Episode (except for duration) nearlyevery day during at least a 1-week period. The mood disturbance issufficiently severe to cause marked impairment in occupationalfunctioning or in usual social activities or relationships with others,or to necessitate hospitalization to prevent harm to self or others, orthere are psychotic features.

The symptoms are not due to the direct physiological effects of asubstance (e.g., a drug of abuse, a medication, or other treatment) or ageneral medical condition (e.g., hyperthyroidism).

D. Criterion A of SZ

See above.

E. Types of SD

The type of SD may be may be specifiable, as either Bipolar Type, if thedisturbance includes a Manic or a Mixed Episode (or a Manic or a MixedEpisode and Major Depressive Episodes), or Depressive Type, if thedisturbance only includes Major Depressive Episodes.

F. Associated Features

Features associated with SD include Learning Problems, Hypoactivity,Psychotic, Euphoric Mood, Depressed Mood, Somatic/Sexual Dysfunction,Hyperactivity, Guilt/Obsession, Odd/Eccentric/Suspicious Personality,Anxious/Fearful/Dependent Personality, and Dramatic/Erratic/AntisocialPersonality.

Schizotypal Personality Disorder (SPD)

Diagnostic Criteria for SPD

A diagnosis of SPD under the criteria of the DSM-IV is generally basedon a pervasive pattern of social and interpersonal deficits marked byacute discomfort with, and reduced capacity for, close relationships aswell as by cognitive or perceptual distortions and eccentricities ofbehavior, beginning by early adulthood and present in a variety ofcontexts, as indicated by five (or more) of the following:

(1) ideas of reference (excluding delusions of reference)

(2) odd beliefs or magical thinking that influences behavior and is

(3) inconsistent with subcultural norms (e.g., superstitiousness, beliefin clairvoyance, telepathy, or “sixth sense;” in children andadolescents, bizarre fantasies or preoccupations)

(4) unusual perceptual experiences, including bodily illusions

(5) odd thinking and speech (e.g., vague, circumstantial, metaphorical,overelaborate, or stereotyped)

(6) suspiciousness or paranoid ideation

(7) inappropriate or constricted affect

(8) behavior or appearance that is odd, eccentric, or peculiar

(9) lack of close friends or confidants other than first-degreerelatives

(10) excessive social anxiety that does not diminish with familiarityand tends to be associated with paranoid fears rather than negativejudgments about self

SPD is diagnosed if the symptoms do not occur exclusively during thecourse of SZ, a Mood Disorder With Psychotic Features, another PsychoticDisorder, or a Pervasive Developmental Disorder, and the disturbance isnot due to the direct physiological effects of a substance (e.g., a drugof abuse, a medication) or a general medical condition.

Associated features of SPD include Depressed Mood andOdd/Eccentric/Suspicious Personality.

Psychiatric Endophenotypes in SZ

A number of endophenotypes, i.e., intermediate phenotypes, that may moreclosely reflect biological mechanisms behind SZ, have been suggested,such as prepulse inhibition, structural abnormalities evident in MRIscans, specific domains of cognition (e.g., executive function), finemotor performance, working memory, etc.

Endophenotypes can also include clinical manifestations such ashallucinations, paranoia, mania, depression, obsessive-compulsivesymptoms, etc., as well as response or lack of response to drugs andcomorbidity for substance and alcohol abuse. See, e.g., Kendler et al.,Am J Psychiatry 152(5):749-54 (1995); Gottesman and Gould, Am JPsychiatry 160(4):636-45 (2003); Cadenhead, Psychiatric Clinics of NorthAmerica. 25(4):837-53 (2002); Gottesman and Gould, American Journal ofPsychiatry. 160(4):636-45 (2003); Heinrichs, Neuroscience &Biobehavioral Reviews. 28(4):379-94 (2004); and Zobel and Maier,Nervenarzt. 75(3):205-14 (2004). There is now evidence that somecandidate genes that were identified using DSM-IV type categoricaldefinitions for “affected” individuals may influence specificendophenotypes, see, e.g., Baker et al., Biol Psychiatry 58(1):23-31(2005); Cannon et al., Arch Gen Psychiatry 62(11):1205-13 (2005);Gothelf et al., Nat Neurosci 8(11):1500-2 (2005); Hallmayer et al., Am JHum Genet 77(3):468-76 (2005); Callicott et al., Proc Natl Acad Sci USA102(24):8627-32 (2005); Gornick et al., J Autism Dev Disord 1-8 (2005).Thus, the methods described herein can be used to associate haplotypeswith specific psychiatric endophenotypes.

Positive and Negative Syndrome Scale (PANSS)

The Positive and Negative Syndrome Scale (PANSS) is a comprehensivepsychometric scale used to classify psychopathology for severeneuropsychiatric diseases, including SZ. It measures a number ofpsychiatric endophenotypes or dimensions using quantitative scales basedon the scoring of patients by clinicians. It is widely used to classifypatients into specific subtypes, and is commonly used for measuring theimprovement of symptoms in response to clinical interventions (Kay etal., Schizophr. Bull. 13:261-276 (1987); Kay et al., Br. J. PsychiatrySuppl 59-67 (1989); Leucht et al., Schizophr. Res. 79:231-238 (2005)).

Detailed information on PANSS and Scoring Criteria can be found in theart, e.g., on the world wide web at panss.org, or in the book by Kay,Positive and Negative Syndromes in Schizophrenia, (Routledge, 1991)which is incorporated herein in its entirety by reference. Based onthese sources, the methodology is summarized briefly below.

PANSS comprises 30 individual subscales. Seven constitute a PositiveSymptom Scale, seven the Negative Symptom Scale, and the remaining 16items make up a General Psychopathology Scale. The scores for thesescales are arrived at by summation of ratings across component items.Therefore, the potential ranges are 7 to 49 for the Positive andNegative Scales, and 16 to 112 for the General Psychopathology Scale(Source: The PANSS Institute).

Each of the 30 items is accompanied by a specific definition as well asdetailed anchoring criteria for all seven rating points. These sevenpoints represent increasing levels of psychopathology, as follows:

1—absent

2—minimal

3—mild

4—moderate

5—moderate severe

6—severe

7—extreme

The PANSS Individual subscales are described below.

P1. DELUSIONS—Beliefs which are unfounded, unrealistic andidiosyncratic.

P2. CONCEPTUAL DISORGANISATION—Disorganized process of thinkingcharacterized by disruption of goal-directed sequencing, e.g.,circumstantiality, loose associations, tangentiality, gross illogicalityor thought block.

P3. HALLUCINATORY BEHAVIOUR—Verbal report or behaviour indicatingperceptions which are not generated by external stimuli. These may occurin the auditory, visual, olfactory or somatic realms.

P4. EXCITEMENT—Hyperactivity as reflected in accelerated motorbehaviour, heightened responsivity to stimuli, hypervigilance orexcessive mood lability.

P5. GRANDIOSITY—Exaggerated self-opinion and unrealistic convictions ofsuperiority, including delusions of extraordinary abilities, wealth,knowledge, fame, power and moral righteousness.

P6. SUSPICIOUSNESS/PERSECUTION—Unrealistic or exaggerated ideas ofpersecution, as reflected in guardedness, ad distrustful attitude,suspicious hypervigilance or frank delusions that others mean harm.

P7. HOSTILITY—Verbal and nonverbal expressions of anger and resentment,including sarcasm, passive-aggressive behavior, verbal abuse andassualtiveness.

N1. BLUNTED AFFECT—Diminished emotional responsiveness as characterizedby a reduction in facial expression, modulation of feelings andcommunicative gestures.

N2. EMOTIONAL WITHDRAWAL—Lack of interest in, involvement with, andaffective commitment to life's events.

N3. POOR RAPPORT—Lack of interpersonal empathy, openness in conversationand sense of closeness, interest or involvement with the interviewer.This is evidenced by interpersonal distancing and reduced verbal andnonverbal communication.

N4. PASSIVE/APATHETIC SOCIAL WITHDRAWAL—Diminished interest andinitiative in social interactions due to passivity, apathy, anergy oravolition. This leads to reduced interpersonal involvements and neglectof activities of daily living.

N5. DIFFICULTY IN ABSTRACT THINKING—Impairment in the use of theabstract-symbolic mode of thinking, as evidenced by difficulty inclassification, forming generalizations and proceeding beyond concreteor egocentric thinking in problem-solving tasks.

N6. LACK OF SPONTANEITY AND FLOW OF CONVERSATION—Reduction in the normalflow of communication associated with apathy, avolition, defensivenessor cognitive deficit. This is manifested by diminished fluidity andproductivity of the verbal interactional process.

N7. STEREOTYPED THINKING—Decreased fluidity, spontaneity and flexibilityof thinking, as evidenced in rigid, repetitious or barren thoughtcontent.

G1. SOMATIC CONCERN—Physical complaints or beliefs about bodily illnessor malfunctions. This may range from a vague sense of ill being toclear-cut delusions of catastrophic physical disease.

G2. ANXIETY—Subjective experience of nervousness, worry, apprehension orrestlessness, ranging from excessive concern about the present or futureto feelings of panic.

G3. GUILT FEELINGS—Sense of remorse or self-blame for real or imaginedmisdeeds in the past.

G4. TENSION—Overt physical manifestations of fear, anxiety, andagitation, such as stiffness, tremor, profuse sweating and restlessness.

G5. MANNERISMS AND POSTURING—Unnatural movements or posture ascharacterized be an awkward, stilted, disorganized, or bizarreappearance.

G6. DEPRESSION—Feelings of sadness, discouragement, helplessness andpessimism.

G7. MOTOR RETARDATION—Reduction in motor activity as reflected inslowing or lessening or movements and speech, diminished responsivenessof stimuli, and reduced body tone.

G8. UNCOOPERATIVENESS—Active refusal to comply with the will ofsignificant others, including the interviewer, hospital staff or family,which may be associated with distrust, defensiveness, stubbornness,negativism, rejection of authority, hostility or belligerence.

G9. UNUSUAL THOUGHT CONTENT—Thinking characterized by strange, fantasticor bizarre ideas, ranging from those which are remote or atypical tothose which are distorted, illogical and patently absurd.

G10. DISORIENTATION—Lack of awareness of one's relationship to themilieu, including persons, place and time, which may be due to confusionor withdrawal.

G11. POOR ATTENTION—Failure in focused alertness manifested by poorconcentration, distractibility from internal and external stimuli, anddifficulty in harnessing, sustaining or shifting focus to new stimuli.

G12. LACK OF JUDGEMENT AND INSIGHT—Impaired awareness or understandingof one's own psychiatric condition and life situation. This is evidencedby failure to recognize past or present psychiatric illness or symptoms,denial of need for psychiatric hospitalization or treatment, decisionscharacterized by poor anticipation or consequences, and unrealisticshort-term and long-range planning.

G13. DISTURBANCE OF VOLITION—Disturbance in the willful initiation,sustenance and control of one's thoughts, behavior, movements andspeech.

G14. POOR IMPULSE CONTROL—Disordered regulation and control of action oninner urges, resulting in sudden, unmodulated, arbitrary or misdirecteddischarge of tension and emotions without concern about consequences.

G15. PREOCCUPATION—Absorption with internally generated thoughts andfeelings and with autistic experiences to the detriment of realityorientation and adaptive behavior.

G16. ACTIVE SOCIAL AVOIDANCE—Diminished social involvement associatedwith unwarranted fear, hostility, or distrust.

Use of PANSS Score for Differential Diagnosis

Each patient's disease manifestation and process is unique. PANSSprovides a structured, objective way of describing the various aspectsof psychopathology of a given patient. However, proper implementation ofthe PANSS requires highly trained personnel to conduct the assessmentand to interpret the results, and there is potential for site to sitevariability, especially outside the research setting.

Each of the PANSS composite scales and subscales can be considered aclinical endophenotype. The ability to link genetic profiles to theseclinical endophenotypes, as described in the examples, will enableclinicians to refine a patient's diagnosis and develop a personalizedtherapeutic strategy for each patient. For example, the “A” allele ofrs4832524, located in the KCNS3 gene, is associated with lower NegativeSymptom burden as shown in the regression analysis in Table 14. Anotherexample is the “A” allele of rs9823803, located in the GADL1 gene, whichis significantly associated with lower scores on the GrandiositySubscale as shown in the regression analysis in Table 15. By identifyingthese genetic contributions to specific endophenotypes, the physiciancan create a personalized diagnosis and treatment regime for thepatient.

Current Treatment of SZ

Subjects with SZ typically require acute treatment for psychoticexacerbations, and long-term treatment including maintenance andprophylactic strategies to sustain symptom improvement and preventrecurrence of psychosis. Subjects with schizoaffective disorderexperience the symptoms of both SZ and affective disorder (manic and/ordepressive), thus require the specific treatments for each disorder.Subjects with SPD sometimes require medication for acute psychoticepisodes but are often treated using psychosocial methods. The methodsdescribed herein can include the administration of one or more acceptedor experimental treatment modalities to a person identified as at riskof developing SZ, SPD, or a SD, based on the presence of a haplotypeassociated with SZ, SPD, or SD. Currently accepted treatments presentlyinclude both pharmacologic and psychosocial management, and occasionallyelectroconvulsive therapy (ECT).

Standard pharmacologic therapies for SZ and SD include theadministration of one or more antipsychotic medications, which aretypically antagonists acting at postsynaptic D2 dopamine receptors inthe brain. Antipsychotic medications include conventional, or firstgeneration, antipsychotic agents, which are sometimes referred to asneuroleptics because of their neurologic side effects, and secondgeneration antipsychotic agents, which are less likely to exhibitneuroleptic effects and have been termed atypical antipsychotics.

In some embodiments, the methods described herein include theadministration of one or more antipsychotic medications to a personidentified by a method described herein as being at risk of developingSZ. Antipsychotic medications substantially reduce the risk of relapsein the stable phase of illness. In some embodiments, the methods includethe administration of a first generation antipsychotic medication at adose that is around the “extrapyramidal symptom (EPS) threshold” (i.e.,the dose that will induce extrapyramidal side effects, e.g.,bradykinesia, rigidity, or dyskinesia, with minimal rigidity detectableon physical examination, and/or a second-generation antipsychotics at adose that is therapeutic, yet below the EPS threshold.

Standard pharmacologic therapies for SD also include the administrationof a combination of antidepressant, and anti-anxiety medication.Suitable antidepressants include serotonergic antidepressants, e.g.,fluoxetine or trazodone. Suitable anxiolytics include benzodiazepines,e.g., lorazepam, clonazepam. Lithium can also be administered. Thus, insome embodiments, the methods can include the administration of one ormore antidepressant and/or anti-anxiety medications to a personidentified as at risk of developing SZ.

The methods can also include psychosocial and rehabilitationinterventions, e.g., interventions that are generally accepted astherapeutically beneficial, e.g., cognitive-behavioral therapy fortreatment-resistant positive psychotic symptoms; supportive,problem-solving, educationally oriented psychotherapy; family therapyand education programs aimed at helping patients and their familiesunderstand the patient's illness, reduce stress, and enhance copingcapabilities; social and living skills training; supported employmentprograms; and/or the provision of supervised residential livingarrangements.

Currently accepted treatments for SZ are described in greater detail inthe Practice Guideline for the Treatment of Patients With Schizophrenia,American Psychiatric Association, Second Edition, American PsychiatricAssociation, 2004, which is incorporated herein by reference in itsentirety.

Methods of Determining Treatment Regimens and Methods of Treating SZ

As described herein, the presence of certain haplotypes described hereinhas been correlated with an increased risk of developing or having SZ;in addition, haplotypes are described herein that are correlated withaltered response to a treatment, e.g., a pharmacological treatment. Analtered response can be, for example, a positive response (i.e., animprovement in one or more symptoms of the disease), negative response(worsening of one or more symptoms of the disease), no response, or thepresence or absence of side effects. Thus, the new methods can alsoinclude selecting a treatment regimen for a subject determined to haveSZ or to be at risk for developing SZ, based upon the absence orpresence of a haplotype described herein. The determination of atreatment regimen can also be based upon the absence or presence ofother risk factors associated with SZ, e.g., as described herein.Therefore, the methods of the invention can include selecting atreatment regimen for a subject having one or more risk factors for SZ,and having a haplotype described herein. The methods can also includeadministering a selected treatment regimen to a subject having, or atrisk for developing, SZ, to thereby treat, prevent or delay furtherprogression of the disease. A treatment regimen can include theadministration of a selected antipsychotic medications to a subjectidentified as at risk of developing SZ, before the onset of anypsychotic episodes. The medications can be selected based on thepresence of a haplotype that is associated with, for example, positiveresponse, or the absence of significant side effects.

As used herein, the term “treat” or “treatment” is defined as theapplication or administration of a treatment regimen, e.g., atherapeutic agent or modality, to a subject, e.g., a patient. Thesubject can be a patient having SZ a symptom of SZ or at risk ofdeveloping (i.e., a predisposition toward) SZ. The treatment can be tocure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate,improve or affect SZ, the symptoms of SZ or the predisposition towardSZ.

The methods described herein, e.g., methods of determining a treatmentregimen and methods of treatment or prevention of SZ can further includethe step of monitoring the subject, e.g., for a change (e.g., anincrease or decrease) in one or more of the diagnostic criteria for SZlisted herein, or any other parameter related to clinical outcome. Thesubject can be monitored in one or more of the following periods: priorto beginning of treatment; during the treatment; or after one or moreelements of the treatment have been administered. Monitoring can be usedto evaluate the need for further treatment with the same or a differenttherapeutic agent or modality. Generally, a decrease in one or more ofthe parameters described above is indicative of the improved conditionof the subject, although with red blood cell and platelet levels, anincrease can be associated with the improved condition of the subject.

The methods can be used, e.g., to evaluate the suitability of, or tochoose between alternative treatments, e.g., a particular dosage, modeof delivery, time of delivery, inclusion of adjunctive therapy, e.g.,administration in combination with a second agent, or generally todetermine the subject's probable drug response genotype. In a preferredembodiment, a treatment for SZ can be evaluated by administering thesame treatment or combinations or treatments to a subject having SZ anda haplotype as described herein and to a subject that has SZ but doesnot have a haplotype as described herein. The effects of the treatmentor combination of treatments on each of these subjects can be used todetermine if a treatment or combination of treatments is particularlyeffective on a sub-group of subjects having SZ. In other embodiments,various treatments or combinations of treatments can be evaluated byadministering two different treatments or combinations of treatments toat least two different subjects having SZ, and a haplotype as describedherein. Such methods can be used to determine if a particular treatmentor combination of treatments is more effective than others in treatingthis subset of SZ patients.

Various treatment regimens are known for treating SZ, e.g., as describedherein.

Pharmacogenomics

With regards to both prophylactic and therapeutic methods of treatmentof SZ, such treatments may be specifically tailored or modified, basedon knowledge obtained from the field of pharmacogenomics.“Pharmacogenomics,” as used herein, refers to the application ofgenomics technologies such as structural chromosomal analysis, to drugsin clinical development and on the market. See, for example, Eichelbaumet al., Clin. Exp. Pharmacol. Physiol. 23:983-985 (1996) and Linder etal., Clin. Chem. 43:254-266 (1997). Specifically, as used herein, theterm refers the study of how a patient's genes determine his or herresponse to a drug (e.g., a patient's “drug response phenotype,” or“drug response genotype”). Thus, another aspect of the inventionprovides methods for tailoring an individual's prophylactic ortherapeutic treatment according to that individual's drug responsegenotype.

Information generated from pharmacogenomic research using a methoddescribed herein can be used to determine appropriate dosage andtreatment regimens for prophylactic or therapeutic treatment of anindividual. This knowledge, when applied to dosing or drug selection,can avoid adverse reactions or therapeutic failure and thus enhancetherapeutic or prophylactic efficiency when administering a therapeuticcomposition, e.g., a cytotoxic agent or combination of cytotoxic agents,to a patient, as a means of treating or preventing SZ.

In one embodiment, a physician or clinician may consider applyingknowledge obtained in relevant pharmacogenomics studies, e.g., using amethod described herein, when determining whether to administer apharmaceutical composition, e.g., an antipsychotic agent or acombination of antipsychotic agents, to a subject. In anotherembodiment, a physician or clinician may consider applying suchknowledge when determining the dosage, e.g., amount per treatment orfrequency of treatments, of a treatment, e.g., a antipsychotic agent orcombination of antipsychotic agents, administered to a patient.

As one example, a physician or clinician may determine (or havedetermined, e.g., by a laboratory) the haplotype of a subject asdescribed herein, and optionally one or more other markers associatedwith SZ of one or a group of subjects who may be participating in aclinical trial, wherein the subjects have SZ, and the clinical trial isdesigned to test the efficacy of a pharmaceutical composition, e.g., anantipsychotic or combination of antipsychotic agents, and wherein thephysician or clinician attempts to correlate the genotypes of thesubjects with their response to the pharmaceutical composition.

As another example, information regarding a haplotype associated with analtered pharmacogenomic response for SZ as described herein, can be usedto stratify or select a subject population for a clinical trial. Theinformation can, in some embodiments, be used to stratify individualsthat may exhibit a toxic response to a treatment from those that willnot. In other cases, the information can be used to separate those thatare more likely to be non-responders from those who will be responders.The haplotypes described herein can be used in pharmacogenomics-baseddesign and to manage the conduct of a clinical trial, e.g., as describedin U.S. Pat. Pub. No. 2003/0108938.

As another example, information regarding a haplotype associated with anincreased risk of SZ, or with altered pharmacogenomic response for SZ,as described herein, can be used to stratify or select human cells orcell lines for drug testing purposes. Human cells are useful forstudying the effect of a polymorphism on physiological function, and foridentifying and/or evaluating potential therapeutic agents for thetreatment of SZ e.g., antipsychotics. Thus the methods can includeperforming the present methods on genetic material from a cell line. Theinformation can, in some embodiments, be used to separate cells thatrespond particular drugs from those that do not respond, e.g. whichcells show altered second messenger signaling.

Theranostics

Also included herein are compositions and methods for the identificationand treatment of subjects who have an increased risk of SZ, or alteredclinical presentation of SZ, such that a theranostic approach can betaken to test such individuals to determine the effectiveness of aparticular therapeutic intervention (e.g., a pharmaceutical ornon-pharmaceutical intervention as described herein) and to alter theintervention to 1) reduce the risk of developing adverse outcomes and 2)enhance the effectiveness of the intervention. Thus, in addition todiagnosing or confirming the predisposition to SZ, the methods andcompositions described herein also provide a means of optimizing thetreatment of a subject having SZ. Provided herein is a theranosticapproach to treating and preventing SZ, by integrating diagnostics andtherapeutics to improve the real-time treatment of a subject.Practically, this means creating tests that can identify which patientsare most suited to a particular therapy, and providing feedback on howwell a drug is working to optimize treatment regimens.

Within the clinical trial setting, a theranostic method or compositionof the invention can provide key information to optimize trial design,monitor efficacy, and enhance drug safety. For instance, “trial design”theranostics can be used for patient stratification, determination ofpatient eligibility (inclusion/exclusion), creation of homogeneoustreatment groups, and selection of patient samples that arerepresentative of the general population. Such theranostic tests cantherefore provide the means for patient efficacy enrichment, therebyminimizing the number of individuals needed for trial recruitment.“Efficacy” theranostics are useful for monitoring therapy and assessingefficacy criteria. Finally, “safety” theranostics can be used to preventadverse drug reactions or avoid medication error.

The methods described herein can include retrospective analysis ofclinical trial data as well, both at the subject level and for theentire trial, to detect correlations between a haplotype as describedherein and any measurable or quantifiable parameter relating to theoutcome of the treatment, e.g., efficacy (the results of which may bebinary (i.e., yes and no) as well as along a continuum), side-effectprofile (e.g., weight gain, metabolic dysfunction, lipid dysfunction,movement disorders, or extrapyramidal symptoms), treatment maintenanceand discontinuation rates, return to work status, hospitalizations,suicidality, total healthcare cost, social functioning scales, responseto non-pharmacological treatments, and/or dose response curves. Theresults of these correlations can then be used to influencedecision-making, e.g., regarding treatment or therapeutic strategies,provision of services, and/or payment. For example, a correlationbetween a positive outcome parameter (e.g., high efficacy, low sideeffect profile, high treatment maintenance/low discontinuation rates,good return to work status, low hospitalizations, low suicidality, lowtotal healthcare cost, high social function scale, favorable response tonon-pharmacological treatments, and/or acceptable dose response curves)and a selected haplotype can influence treatment such that the treatmentis recommended or selected for a subject having the selected haplotype.

Kits

Also within the scope of the invention are kits comprising a probe thathybridizes with a region of human chromosome as described herein and canbe used to detect a polymorphism described herein. The kit can includeone or more other elements including: instructions for use; and otherreagents, e.g., a label, or an agent useful for attaching a label to theprobe. Instructions for use can include instructions for diagnosticapplications of the probe for assessing risk of SZ in a method describedherein. Other instructions can include instructions for attaching alabel to the probe, instructions for performing in situ analysis withthe probe, and/or instructions for obtaining a sample to be analyzedfrom a subject. As discussed above, the kit can include a label, e.g.,any of the labels described herein. In some embodiments, the kitincludes a labeled probe that hybridizes to a region of human chromosomeas described herein, e.g., a labeled probe as described herein.

The kit can also include one or more additional probes that hybridize tothe same chromosome, e.g., chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15,15, 17, 18, 19, or 20, or another chromosome or portion thereof that canhave an abnormality associated with risk for SZ. For example, theadditional probe or probes can be: a probe that hybridizes to humanchromosome 22q11-12 or a portion thereof, (e.g., a probe that detects asequence associated with SZ or BD in this region of chromosome 22), orprobes that hybridize to all or a portion of 22q12.3 (e.g., nearD22S283), 22q11.2, 22q11.2, 22q11-q13, 1q42.1, 1q42.1, 1q21-q22, 2p, 2q,3p25, 4p, 4q, 5q11.2-q13.3, 6p22.3, 6p23, 6q13-q26, 7q, 8p12-21, 8q, 9p,10p15-p13 (e.g., near D105189), 10q22.3, 11q14-q21, 12q24, 13q34, 13q32,14q32.3, 15q15, 16p, 17q, 18p, 18q, 19p. 20p, 21q, Xq, and/or the X/Ypseudoautosomal region. A kit that includes additional probes canfurther include labels, e.g., one or more of the same or differentlabels for the probes. In other embodiments, the additional probe orprobes provided with the kit can be a labeled probe or probes. When thekit further includes one or more additional probe or probes, the kit canfurther provide instructions for the use of the additional probe orprobes.

Kits for use in self-testing can also be provided. For example, suchtest kits can include devices and instructions that a subject can use toobtain a sample, e.g., of buccal cells or blood, without the aid of ahealth care provider. For example, buccal cells can be obtained using abuccal swab or brush, or using mouthwash.

Kits as provided herein can also include a mailer, e.g., a postage paidenvelope or mailing pack, that can be used to return the sample foranalysis, e.g., to a laboratory. The kit can include one or morecontainers for the sample, or the sample can be in a standard bloodcollection vial. The kit can also include one or more of an informedconsent form, a test requisition form, and instructions on how to usethe kit in a method described herein. Methods for using such kits arealso included herein. One or more of the forms, e.g., the testrequisition form, and the container holding the sample, can be coded,e.g., with a bar code, for identifying the subject who provided thesample.

Databases

Also provided herein are databases that include a list of polymorphismsas described herein, and wherein the list is largely or entirely limitedto polymorphisms identified as useful in performing genetic diagnosis ofor determination of susceptibility to SZ as described herein. The listis stored, e.g., on a flat file or computer-readable medium. Thedatabases can further include information regarding one or moresubjects, e.g., whether a subject is affected or unaffected, clinicalinformation such as endophenotype, age of onset of symptoms, anytreatments administered and outcomes (e.g., data relevant topharmacogenomics, diagnostics or theranostics), and other details, e.g.,about the disorder in the subject, or environmental or other geneticfactors. The databases can be used to detect correlations between aparticular haplotype and the information regarding the subject, e.g., todetect correlations between a haplotype and a particular endophenotype,or treatment response.

Engineered Cells

Also provided herein are engineered cells that harbor one or morepolymorphism described herein, e.g., one or more polymorphisms thatconstitute a haplotype associated with SZ, altered drug response or aspecific endophenotype. Such cells are useful for studying the effect ofa polymorphism on physiological function, and for identifying and/orevaluating potential therapeutic agents for the treatment of SZ-spectrumdisorders e.g., anti-psychotics.

As one example, included herein are cells in which one of the variousalleles of the genes described herein has be re-created that isassociated with an increased risk of SZ. Methods are known in the artfor generating cells, e.g., by homologous recombination between theendogenous gene and an exogenous DNA molecule introduced into a cell,e.g., a cell of an animal. In some embodiments, the cells can be used togenerate transgenic animals using methods known in the art.

The cells are preferably mammalian cells, e.g., neuronal type cells, inwhich an endogenous gene has been altered to include a polymorphism asdescribed herein. Techniques such as targeted homologous recombinations,can be used to insert the heterologous DNA as described in, e.g.,Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published in May 16,1991.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Example 1 Novel Markers Associated with SZ

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE),a large federally funded clinical trial designed to assess the efficacyof antipsychotics in a real world setting, is a valuable resource fordetermining the role of genes in drug response (Stroup et al.,Schizophr. Bull. 29:15-31 (2003); Lieberman et al., N. Engl. J. Med.353:1209-1223 (2005)). As part of the CATIE trial, SNP genotyping wasperformed for roughly half of the trial participants (Sullivan et al.,Mol. Psychiatry 13:570-584 (2008)). When combined with disease status,PANSS scores, and clinical drug response data, the genotyping dataallows the identification of genetic variants (e.g., SNPs) that arestatistically associated with increased risk of developing SZ.

The design of the CATIE study has been described in detail by others(see, e.g., Stroup et al., Schizophr. Bull. 29:15-31 (2003); Liebermanet al., N. Engl. J. Med. 353:1209-1223 (2005)). Briefly, 1460 subjectswere randomly assigned one of several antipsychotics and those who didnot respond or chose to quit their current medication were re-randomizedto another drug. Details regarding SNP genotyping and quality controlhave been recently published (Sullivan et al., Mol. Psychiatry13:570-584 (2008)).

Genotype and phenotype data for the CATIE trial were made available toqualified researchers through the NIMH Center for Collaborative GeneticStudies on Mental Disorders. Data for 417 patients with schizophreniaand 419 unaffected controls self reported as having exclusively Europeanancestry were evaluated. This same patient population was described in arecent study by Sullivan and coworkers, which confirmed that there is nohidden stratification in the sample (Sullivan et al., Mol. Psychiatry13:570-584 (2008)).

In addition, for this example, genotyping and phenotype data wereobtained from the Genetic Analysis Information Network (GAIN) Databasefound at ncbi.nlm.nih.gov through dbGaP, at accession numberPHS000017.v1.p1. Genotypes and associated phenotype data for the GAINGenome-Wide Association Study of Schizophrenia were provided by P.Gejman, and genotyping of these samples was provided through the GeneticAssociation Information Network (GAIN). Data for 1172 cases and 1378controls with Caucasian ancestry were evaluated for the GAIN sample.

For both the CATIE and GAIN studies, individual cases were diagnosed ashaving SZ based on DSM-III/IV criteria.

Statistical Methods:

Genetic analysis to document the influence of haplotypes on SZ risk wasperformed using the PLINK 1.03 whole genome analysis toolset developedby Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81:559-575(2007)). PLINK calculates P values for the allele-specific chi-squaredtest and the odds ratio (OR; or relative risk) associated with the minorallele.

Confirmation of Novel Markers Associated with SZ Risk:

Table 1 provides numerous examples of SNP-based alleles that influenceSZ risk. Table 1 reports the minor allele frequencies, P values, and ORsfor numerous SNPs, in Tables B and C, that affect SZ risk. ORs of >1.0indicate that the minor SNP allele is associated with greatersusceptibility, and ORs of <1.0 indicate that the minor SNP allele isassociated with decreased susceptibility to SZ.

Note in Table 1 that haplotype blocks result in the same Test SNP beingin linkage disequilibrium with multiple SNPs in Table B. Similarly,haplotype blocks result in multiple Test SNPs that can be used for eachSNP listed in Table B, though such redundant examples are not presentedin Table 1, unless the test SNP was evaluated in both the CATIE and GAINsamples.

TABLE 1 Confirmation of Novel Markers Associated with SZ risk Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² AlleleCases P OR Study CAMTA1 rs10864639 rs1542899 1.00 C 0.086 0.008304 0.78GAIN CAMTA1 rs845197 rs2097518 0.71 C 0.249 0.02548 0.87 GAIN CAMTA1rs2071986 rs9919223 1.00 T 0.267 0.0347 0.88 GAIN RERE rs12136689rs10779702 0.76 A 0.355 0.006746 1.18 GAIN RERE rs8627 rs10779702 0.52 A0.355 0.006746 1.18 GAIN RP1-21O18.1 rs7546786 rs7546786 N/A C 0.2110.0356 0.78 CATIE RP1-21O18.1 rs2073091 rs761288 0.69 C 0.269 0.046541.14 GAIN RP1-21O18.1 rs4661572 rs761288 0.56 C 0.269 0.04654 1.14 GAINRP1-21O18.1 rs12057431 rs10803343 1.00 C 0.016 0.03243 3.20 CATIE KCND3rs4838924 rs1373291 0.86 T 0.224 0.04121 1.28 CATIE VAMP4 rs10913530rs9943293 1.00 T 0.311 0.01885 1.29 CATIE VAMP4 rs12096984 rs99432931.00 T 0.311 0.01885 1.29 CATIE VAMP4 rs2073484 rs9943293 1.00 T 0.3110.01885 1.29 CATIE VAMP4 rs6672082 rs9943293 1.00 T 0.311 0.01885 1.29CATIE VAMP4 rs15655 rs10913529 1.00 C 0.182 0.00696 0.83 GAIN DNM3rs2093184 rs7540873 0.62 T 0.282 0.03038 0.88 GAIN DNM3 rs7554526rs7540873 0.61 T 0.282 0.03038 0.88 GAIN DNM3 rs9425287 rs10158839 1.00C 0.513 0.04037 1.12 GAIN FASLG rs10458360 rs10458360 N/A G 0.4740.02088 1.14 GAIN FASLG rs12135884 rs10458360 0.56 G 0.474 0.02088 1.14GAIN CACNA1E rs553042 rs553042 N/A G 0.304 0.006968 1.18 GAIN CACNA1Ers17494681 rs17494681 N/A A 0.188 0.01055 1.21 GAIN CACNA1E rs506947rs7554158 1.00 A 0.109 0.01115 0.80 GAIN CACNA1E rs638132 rs546191 0.67T 0.193 0.01582 0.75 CATIE CAMK1G rs6690557 rs9429821 0.69 C 0.3170.04072 0.88 GAIN SYT14 rs9429830 rs7543650 0.52 T 0.236 0.02059 0.77CATIE SYT14 rs9429830 rs227193 0.90 G 0.400 0.0183 0.87 GAIN KCNH1rs1770220 rs1340127 0.51 G 0.437 0.01888 0.87 GAIN ANK3 rs1050745rs1050745 N/A T 0.209 0.02123 0.86 GAIN ANK3 rs2393607 rs1078534 0.82 C0.173 0.01647 0.74 CATIE ANK3 rs11596260 rs11596260 N/A T 0.351 0.037730.89 GAIN ANK3 rs2241540 rs11596260 1.00 T 0.351 0.03773 0.89 GAIN ANK3rs1551684 rs1551683 1.00 T 0.114 0.0462 0.75 CATIE KCNQ1 rs2283174rs2283179 0.52 C 0.132 0.04204 1.19 GAIN KCNQ1 rs231348 rs10832405 0.80A 0.126 0.0203 1.45 CATIE RHOG rs11030008 rs1869002 0.67 G 0.3120.007693 1.34 CATIE USH1C rs2237965 rs1076311 0.63 G 0.472 0.03922 1.23CATIE USH1C rs10766408 rs2237959 0.53 G 0.454 0.01149 1.29 CATIE USH1Crs2041027 rs10766410 0.54 A 0.461 0.0002016 1.45 CATIE USH1C rs2237957rs10766410 0.62 A 0.461 0.0002016 1.45 CATIE OTOG rs10766410 rs10766410N/A A 0.461 0.0002016 1.45 CATIE OTOG rs2073582 rs10766410 0.55 A 0.4610.0002016 1.45 CATIE SERGEF rs4757589 rs4757589 N/A G 0.497 0.0016051.19 GAIN NAV2 rs10766590 rs10500860 0.59 G 0.308 0.02614 1.15 GAIN NAV2rs2042600 rs1559665 0.93 T 0.480 0.02766 0.88 GAIN NAV2 rs2278132rs1559665 0.87 T 0.480 0.02766 0.88 GAIN NAV2 rs7119267 rs7119267 N/A C0.346 0.02078 1.15 GAIN NAV2 rs2028570 rs2255677 0.58 A 0.441 0.016651.15 GAIN NAV2 rs2289566 rs10732471 0.57 A 0.227 0.009299 0.84 GAINSLC17A6 rs11026532 rs1155331 0.96 T 0.265 0.02007 0.86 GAIN LRRC4Crs1551833 rs4237678 0.54 C 0.188 0.002021 1.26 GAIN LRRC4C rs10837367rs1377106 1.00 A 0.067 0.00126 0.57 CATIE HSD17B12 rs1061810 rs71166410.54 G 0.346 0.02577 1.27 CATIE HSD17B12 rs4755744 rs7116641 0.65 G0.346 0.02577 1.27 CATIE HSD17B12 rs10838160 rs10838166 1.00 G 0.3830.003094 0.75 CATIE HSD17B12 rs3802891 rs10838166 1.00 G 0.383 0.0030940.75 CATIE PHACS rs16937817 rs7950395 0.58 A 0.141 0.00271 1.29 GAINPHACS rs7950395 rs7950395 N/A A 0.141 0.00271 1.29 GAIN SYT13 rs12362429rs7124508 0.64 A 0.425 0.02358 0.88 GAIN SYT13 rs11038382 rs1077491 1.00T 0.290 0.0195 0.78 CATIE SYT13 rs2863182 rs1077491 0.84 T 0.290 0.01950.78 CATIE SYT13 rs4992029 rs1077491 0.61 T 0.290 0.0195 0.78 CATIESYT13 rs12362429 rs7118408 0.70 G 0.419 0.01028 0.78 CATIE ZFP91-CNTFrs1938596 rs2509920 0.97 G 0.404 0.01056 0.86 GAIN ZFP91-CNTF rs4319530rs2509920 0.90 G 0.404 0.01056 0.86 GAIN ZFP91-CNTF rs7945889 rs9485620.95 G 0.160 0.04957 0.86 GAIN ZFP91-CNTF rs948562 rs948562 N/A G 0.1600.04957 0.86 GAIN DTX4 rs1048444 rs3847 1.00 A 0.353 0.01537 0.87 GAINDTX4 rs2211912 rs3847 0.77 A 0.353 0.01537 0.87 GAIN DTX4 rs3847 rs3847N/A A 0.353 0.01537 0.87 GAIN DTX4 rs5029315 rs3847 0.77 A 0.353 0.015370.87 GAIN DTX4 rs544864 rs3847 0.55 A 0.353 0.01537 0.87 GAIN DTX4rs621162 rs3847 0.55 A 0.353 0.01537 0.87 GAIN DTX4 rs656163 rs3847 0.64A 0.353 0.01537 0.87 GAIN KIAA1853 rs1568923 rs7298478 0.69 G 0.2750.006263 0.84 GAIN KIAA1853 rs7134748 rs4767783 0.72 A 0.404 0.037281.13 GAIN KIAA1853 rs7969288 rs4767783 0.57 A 0.404 0.03728 1.13 GAINKIAA1853 rs7297606 rs4075945 1.00 T 0.093 0.01915 1.27 GAIN RIMBP2rs4237817 rs1877986 0.62 T 0.415 0.0264 0.80 CATIE CHFR rs2306541rs7297261 0.96 A 0.315 0.04659 1.13 GAIN TTC5 rs3737220 rs4981948 1.00 C0.175 0.006939 0.82 GAIN TTC5 rs2318864 rs4981951 0.52 C 0.185 0.016890.84 GAIN TTC5 rs3742945 rs4981951 0.52 C 0.185 0.01689 0.84 GAIN DACT1rs11541 rs863091 1.00 A 0.202 0.04207 1.16 GAIN DACT1 rs160472 rs8630910.54 A 0.202 0.04207 1.16 GAIN DACT1 rs863091 rs863091 N/A A 0.2020.04207 1.16 GAIN DAAM1 rs4127823 rs12590850 0.61 A 0.416 0.02325 1.26CATIE GPR135 rs10138199 rs1273156 0.81 T 0.459 0.02265 1.25 CATIE GPR135rs1253181 rs1273156 1.00 T 0.459 0.02265 1.25 CATIE GPR135 rs17255731rs1273156 0.62 T 0.459 0.02265 1.25 CATIE GPR135 rs4898989 rs12731560.81 T 0.459 0.02265 1.25 CATIE GPR135 rs9323348 rs1273156 0.81 T 0.4590.02265 1.25 CATIE EML1 rs2273704 rs12590861 0.61 G 0.311 0.00485 1.19GAIN EML1 rs7143905 rs12590861 0.70 G 0.311 0.00485 1.19 GAIN EML1rs746698 rs11850280 0.91 G 0.190 0.008545 1.21 GAIN EML1 rs11160553rs12435250 0.67 G 0.254 0.02602 0.87 GAIN EML1 rs12433613 rs124352500.56 G 0.254 0.02602 0.87 GAIN EML1 rs6575751 rs12435250 0.67 G 0.2540.02602 0.87 GAIN EVL rs3206354 rs3206354 N/A T 0.053 0.03254 1.33 GAINHERC2 rs11074322 rs6497272 1.00 G 0.017 0.03882 2.82 CATIE HERC2rs1635168 rs8041209 0.87 T 0.087 0.0183 1.57 CATIE HERC2 rs2238289rs8041209 0.51 T 0.087 0.0183 1.57 CATIE HERC2 rs7495174 rs8041209 0.58T 0.087 0.0183 1.57 CATIE HERC2 rs11631797 rs916977 0.86 T 0.195 0.039811.30 CATIE HERC2 rs916977 rs916977 N/A T 0.195 0.03981 1.30 CATIE UNC13Crs2115827 rs12148800 0.97 C 0.470 0.02906 0.88 GAIN UNC13C rs2163195rs2115825 0.57 A 0.501 0.02333 1.14 GAIN UNC13C rs12594549 rs934192 0.85T 0.175 0.001305 1.28 GAIN UNC13C rs1897069 rs1897069 N/A C 0.4490.01113 0.87 GAIN UNC13C rs12910912 rs12900128 0.52 G 0.295 0.01764 1.16GAIN UNC13C rs11856476 rs12917023 0.70 G 0.172 0.04217 1.17 GAIN NEDD4rs4424863 rs4520787 0.90 A 0.397 0.03785 1.24 CATIE NEDD4 rs8028559rs11630780 0.69 C 0.396 0.01945 0.79 CATIE NEDD4 rs17238461 rs21751040.53 A 0.108 0.03922 1.42 CATIE NEDD4 rs1509408 rs1509408 N/A C 0.2250.03142 0.78 CATIE AKAP13 rs2291049 rs16941653 0.59 T 0.070 0.01822 0.66CATIE AKAP13 rs338556 rs2241266 1.00 T 0.071 0.0406 0.81 GAIN KLHL25rs2430838 rs2241266 0.91 T 0.071 0.0406 0.81 GAIN SV2B rs1075840rs2269799 0.72 C 0.325 0.004465 1.36 CATIE SV2B rs1117388 rs2269799 0.55C 0.325 0.004465 1.36 CATIE SV2B rs2301665 rs2269799 0.59 C 0.3250.004465 1.36 CATIE SV2B rs8027498 rs2269799 0.72 C 0.325 0.004465 1.36CATIE SV2B rs3743444 rs2239994 0.50 T 0.113 0.01159 1.53 CATIE SLCO3A1rs12912997 rs12905912 0.96 A 0.297 0.03912 0.81 CATIE IGF1R rs4965436rs11634874 0.76 C 0.111 0.02439 1.46 CATIE IGF1R rs11247380 rs71651810.55 G 0.194 0.03684 0.78 CATIE IGF1R rs1879613 rs7165181 0.96 G 0.1940.03684 0.78 CATIE N4BP1 rs1039342 rs8046716 0.61 T 0.500 0.003166 1.34CATIE N4BP1 rs1120276 rs8046716 0.61 T 0.500 0.003166 1.34 CATIE N4BP1rs1224 rs8046716 0.61 T 0.500 0.003166 1.34 CATIE N4BP1 rs2354580rs8046716 1.00 T 0.500 0.003166 1.34 CATIE N4BP1 rs3826176 rs80467161.00 T 0.500 0.003166 1.34 CATIE N4BP1 rs9937623 rs8046716 0.59 T 0.5000.003166 1.34 CATIE NDRG4 rs13333449 rs16960170 0.80 G 0.311 0.021371.15 GAIN NDRG4 rs7202037 rs16960170 0.67 G 0.311 0.02137 1.15 GAINKIAA0182 rs736845 rs736845 N/A A 0.310 0.0005682 1.24 GAIN KIAA0182rs9940601 rs9940601 N/A A 0.403 0.01452 1.15 GAIN KIAA0182 rs3815794rs1053328 0.73 A 0.327 0.00984 0.86 GAIN KIAA0182 rs3815794 rs10533280.73 T 0.315 0.002786 0.74 CATIE C16orf74 rs11644122 rs11644122 N/A T0.293 0.03696 0.88 GAIN C16orf74 rs2305357 rs394623 0.55 G 0.4030.0003797 1.23 GAIN C16orf74 rs373835 rs394623 0.68 G 0.403 0.00037971.23 GAIN C16orf74 rs386061 rs394623 0.68 G 0.403 0.0003797 1.23 GAINPMP22 rs13422 rs230915 0.76 C 0.413 0.03188 1.13 GAIN PMP22 rs230938rs230915 0.97 C 0.413 0.03188 1.13 GAIN PMP22 rs231021 rs230915 0.55 C0.413 0.03188 1.13 GAIN FUSSEL18 rs10502880 rs8086549 0.85 C 0.4730.04802 1.22 CATIE FUSSEL18 rs17785419 rs8086549 0.85 C 0.473 0.048021.22 CATIE FUSSEL18 rs2668771 rs8086549 0.64 C 0.473 0.04802 1.22 CATIEFUSSEL18 rs7236105 rs8086549 1.00 C 0.473 0.04802 1.22 CATIE SMAD2rs12457664 rs1792670 0.85 G 0.445 0.039 0.89 GAIN SMAD2 rs1787176rs1792670 0.97 G 0.445 0.039 0.89 GAIN SMAD2 rs1792666 rs1792670 0.71 G0.445 0.039 0.89 GAIN SMAD2 rs1792682 rs1792670 0.94 G 0.445 0.039 0.89GAIN SMAD2 rs2000709 rs1792670 0.84 G 0.445 0.039 0.89 GAIN SMAD2rs7228393 rs1792670 0.91 G 0.445 0.039 0.89 GAIN KIAA0427 rs2175565rs9952398 1.00 C 0.253 0.003642 1.41 CATIE KIAA0427 rs8095199 rs13842270.51 C 0.254 0.004491 0.84 GAIN KIAA0427 rs8095199 rs8083702 0.51 C0.251 0.04846 0.80 CATIE SMAD4 rs12458752 rs1789223 0.53 G 0.365 0.035360.89 GAIN SMAD4 rs12958604 rs1789223 0.53 G 0.365 0.03536 0.89 GAINSMAD4 rs2276163 rs1789223 0.53 G 0.365 0.03536 0.89 GAIN SMAD4 rs2298617rs1789223 0.53 G 0.365 0.03536 0.89 GAIN SMAD4 rs3764465 rs1789223 0.53G 0.365 0.03536 0.89 GAIN DCC rs1893572 rs882333 0.76 T 0.326 0.032941.26 CATIE BMP7 rs162316 rs162313 0.57 T 0.109 0.01705 0.81 GAIN BMP7rs162316 rs6127980 0.57 A 0.152 0.03952 1.35 CATIE

Example 2 Novel Markers Associated with Olanzapine Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on olanzapineresponse was performed using as described in Example 1 with the PLINK1.03 whole genome analysis toolset developed by Purcell and coworkers(Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). PLINK calculatesP values for the allele-specific chi-squared test and the odds ratio(OR; or relative risk) associated with the minor allele.

Confirmation of SNP Effects on Olanzapine Response and Side Effects:

Tables 2 and 3 report the minor allele frequencies, P values, and ORsfor SNPs in Tables B and C, that affect olanzapine response and sideeffect rates, respectively. Note in Tables 2 and 3 that haplotype blocksresult in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B. Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 2 and 3.

Tables 2 and 3, provide numerous examples of SNP-based alleles thatpredict altered response to olanzapine. For Table 2, ORs of >1.0indicate that the minor SNP allele is associated with greater clinicalimprovement, and ORs of <1.0 indicate that the minor SNP allele isassociated with decreased susceptibility. For Table 3 ORs of >1.0indicate that the minor SNP allele is associated with an increase instudy ending side effects, and ORs of <1.0 indicate that the minor SNPallele is associated a decrease in study ending side effects.

TABLE 2 Alleles Affecting Positive Response to Olanzapine Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Alleleresponders P OR CAMTA1 rs449250 rs277675 0.82 C 0.306 0.01603 0.47CAMTA1 rs6577393 rs6657847 0.51 T 0.264 0.01963 0.47 CAMTA1 rs6577401rs4243823 0.53 A 0.361 0.0152 0.48 CAMTA1 rs7554752 rs10864255 0.96 T0.458 0.0121 2.18 PER3 rs2640909 rs228652 0.70 A 0.361 0.01662 2.21RP1-21O18.1 rs4661572 rs1000313 0.63 G 0.250 0.01139 2.69 RP1-21O18.1rs6674129 rs6665012 0.74 G 0.347 0.0226 0.50 KCND3 rs197422 rs1974120.94 C 0.556 0.02599 1.96 KCND3 rs3738298 rs544941 0.65 T 0.206 0.048452.29 DNM3 rs10489730 rs10910966 1.00 C 0.444 0.0202 2.06 DNM3 rs10752946rs1063412 0.97 G 0.542 0.04115 1.85 DNM3 rs3736791 rs10910966 0.93 C0.444 0.0202 2.06 DNM3 rs4576686 rs10910966 0.79 C 0.444 0.0202 2.06SYT14 rs11119426 rs6701631 1.00 T 0.250 0.01892 2.48 DPH3 rs2245708rs2470508 0.97 T 0.514 0.0172 2.06 DPH3 rs2245721 rs842254 1.00 T 0.3430.02042 0.49 DPH3 rs842257 rs842254 1.00 T 0.343 0.02042 0.49 DPH3rs859703 rs842254 1.00 T 0.343 0.02042 0.49 ANK3 rs10733757 rs107614460.90 C 0.306 0.01208 2.44 ANK3 rs4568956 rs10761446 0.57 C 0.306 0.012082.44 ANK3 rs7907721 rs10761446 0.50 C 0.306 0.01208 2.44 USH1C rs16770rs2237961 0.92 C 0.042 0.02566 0.26 NAV2 rs2585788 rs2625312 0.84 A0.292 0.04703 2.02 DAAM1 rs10143918 rs6573250 0.69 T 0.542 0.00853 2.22DAAM1 rs1252989 rs7143953 0.67 T 0.286 0.03629 0.51 DAAM1 rs1253005rs7143953 0.66 T 0.286 0.03629 0.51 DAAM1 rs1268579 rs17096088 0.60 G0.069 0.03473 0.34 DAAM1 rs4127823 rs12589351 0.61 C 0.528 0.03651 1.88DAAM1 rs4901909 rs7143953 0.60 T 0.286 0.03629 0.51 DAAM1 rs8022614rs7143953 0.93 T 0.286 0.03629 0.51 DAAM1 rs941884 rs7143953 0.51 T0.286 0.03629 0.51 GPR135 rs10136708 rs1253170 0.67 T 0.556 0.01391 2.10GPR135 rs10138199 rs1253170 0.54 T 0.556 0.01391 2.10 GPR135 rs1253181rs1253170 0.74 T 0.556 0.01391 2.10 GPR135 rs17255731 rs1273156 0.62 T0.597 0.03629 1.88 GPR135 rs4898989 rs1253170 0.54 T 0.556 0.01391 2.10GPR135 rs9323348 rs1253170 0.54 T 0.556 0.01391 2.10 EML1 rs11160553rs11623084 0.88 C 0.485 0.0387 1.91 EML1 rs12433613 rs11623084 0.77 C0.485 0.0387 1.91 EML1 rs2250718 rs10150225 0.53 T 0.667 0.01353 2.14EML1 rs2273707 rs10150225 1.00 T 0.667 0.01353 2.14 EML1 rs6575751rs11623084 0.88 C 0.485 0.0387 1.91 HERC2 rs1635168 rs8041209 0.87 T0.028 0.02867 0.21 HERC2 rs2238289 rs8041209 0.51 T 0.028 0.02867 0.21HERC2 rs7495174 rs8041209 0.58 T 0.028 0.02867 0.21 UNC13C rs12910912rs12900128 0.52 C 0.361 0.01107 2.34 NEDD4 rs2303579 rs10518831 0.51 G0.194 0.02723 2.61 NEDD4 rs2303580 rs10518831 0.51 G 0.194 0.02723 2.61SV2B rs11630131 rs1002556 0.83 C 0.250 0.01139 2.69 SV2B rs2073967rs1002556 0.51 C 0.250 0.01139 2.69 SLCO3A1 rs1517618 rs207954 0.72 T0.167 0.00355 0.35 SLCO3A1 rs2176452 rs8027160 0.58 G 0.444 0.02815 1.98IGF1R rs4966020 rs11633717 0.88 C 0.236 0.02174 0.47 IGF1R rs7174918rs11633717 0.88 C 0.236 0.02174 0.47 IGF1R rs8038015 rs11633717 0.82 C0.236 0.02174 0.47 NDRG4 rs1058132 rs1058132 N/A T 0.371 0.02093 2.15NDRG4 rs2271948 rs1058132 0.74 T 0.371 0.02093 2.15 NDRG4 rs2280397rs1058132 0.92 T 0.371 0.02093 2.15 C16orf74 rs2305357 rs442069 0.77 G0.250 0.00821 0.42 C16orf74 rs373835 rs442069 0.93 G 0.250 0.00821 0.42C16orf74 rs386061 rs442069 1.00 G 0.250 0.00821 0.42 C16orf74 rs386061rs386061 N/A C 0.278 0.01847 0.47 KIAA0427 rs8094634 rs1023943 0.72 T0.208 0.0413 0.49 SMAD7 rs11874392 rs12953717 0.65 T 0.528 0.02717 1.95SMAD7 rs736839 rs2337153 0.73 A 0.486 0.00224 2.59 DYM rs498929 rs5779790.96 A 0.125 0.01752 0.38 DYM rs833503 rs577979 0.53 A 0.125 0.017520.38 NDRG4 rs1058132 rs1058132 N/A T 0.371 0.02093 2.15 UNC13Crs12910912 rs12910912 N/A G 0.250 0.01139 2.69 SV2B rs11630131rs11630131 N/A A 0.222 0.01349 2.78

TABLE 3 Alleles Affecting Negative Side Effects for Olanzapine Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Allelediscontinuers P OR CAMTA1 rs1417986 rs2301488 0.54 T 0.630 0.03409 2.08CAMTA1 rs7554752 rs17030082 0.63 A 0.239 0.02475 0.43 DNM3 rs10752946rs1063412 0.97 G 0.283 0.009837 0.39 DNM3 rs13932 rs9425606 0.75 G 0.1300.007451 0.30 DNM3 rs2206543 rs6690848 0.52 G 0.500 0.03358 2.06 DNM3rs4075021 rs12075807 0.71 G 0.565 0.03158 2.09 DNM3 rs4382763 rs40721171.00 C 0.326 0.01406 2.55 DNM3 rs6701033 rs6690848 0.52 G 0.500 0.033582.06 DNM3 rs965051 rs6690848 0.52 G 0.500 0.03358 2.06 RHOG rs11030008rs11030008 N/A G 0.522 0.01711 2.25 RHOG rs1451722 rs11030008 0.76 G0.522 0.01711 2.25 RHOG rs11030008 rs11030008 N/A G 0.522 0.01711 2.25OTOG rs1003490 rs11024348 0.77 T 0.370 0.003588 2.93 OTOG rs10832824rs11024348 0.52 T 0.370 0.003588 2.93 OTOG rs11024357 rs869108 0.85 G0.370 0.0001953 4.10 OTOG rs11024358 rs869108 0.85 G 0.370 0.00019534.10 OTOG rs2023483 rs11024348 0.50 T 0.370 0.003588 2.93 OTOGrs11024357 rs11024357 N/A C 0.370 0.0001953 4.10 NAV2 rs2585788rs2625312 0.84 A 0.065 0.00435 0.19 NAV2 rs6483629 rs12099330 0.59 T0.261 0.0278 2.47 NAV2 rs7125647 rs2119981 0.61 A 0.238 0.004283 0.33ULK1 rs11616018 rs10794440 0.51 G 0.087 0.02249 0.30 ULK1 rs9652059rs10794440 0.55 G 0.087 0.02249 0.30 TTC5 rs1953552 rs11623837 0.60 G0.261 0.02693 0.44 TEP1 rs1713418 rs1713419 1.00 G 0.283 0.04278 0.48DAAM1 rs4127823 rs12589351 0.61 C 0.304 0.04536 0.49 GPR135 rs10136708rs1253170 0.67 T 0.304 0.0307 0.46 GPR135 rs10138199 rs1253170 0.54 T0.304 0.0307 0.46 GPR135 rs1253181 rs1253170 0.74 T 0.304 0.0307 0.46GPR135 rs4898989 rs1253170 0.54 T 0.304 0.0307 0.46 GPR135 rs9323348rs1253170 0.54 T 0.304 0.0307 0.46 RTN1 rs10145080 rs12878097 0.55 C0.087 0.01469 0.28 RTN1 rs12717467 rs17731838 0.52 T 0.087 0.01821 0.29RTN1 rs17310036 rs1957311 0.79 A 0.182 0.008994 0.34 EVL rs4905933rs10148930 0.85 A 0.283 0.004807 0.36 EVL rs726514 rs10148930 0.85 A0.283 0.004807 0.36 HERC2 rs1635168 rs2346050 0.87 C 0.152 0.03438 3.05HERC2 rs2238289 rs2346050 0.51 C 0.152 0.03438 3.05 HERC2 rs7495174rs2346050 0.58 C 0.152 0.03438 3.05 UNC13C rs11856476 rs8024165 0.84 T0.413 0.01984 2.28 UNC13C rs12594549 rs2115820 0.90 G 0.068 0.04824 0.30UNC13C rs12914912 rs8024165 0.63 T 0.413 0.01984 2.28 UNC13C rs4776216rs8024165 0.52 T 0.413 0.01984 2.28 NEDD4 rs17238461 rs9972348 0.57 G0.326 0.04861 2.10 Gcom1 rs1908202 rs2470360 0.64 T 0.413 0.03002 2.15GRINL1A rs2069133 rs1873993 0.84 G 0.522 0.02761 2.12 ADAM10 rs3764196rs7164844 0.51 C 0.043 0.02586 0.21 N4BP1 rs1039342 rs8046716 0.61 T0.348 0.04956 0.50 N4BP1 rs1120276 rs8046716 0.61 T 0.348 0.04956 0.50N4BP1 rs1224 rs8046716 0.61 T 0.348 0.04956 0.50 N4BP1 rs2354580rs8046716 1.00 T 0.348 0.04956 0.50 N4BP1 rs3826176 rs8046716 1.00 T0.348 0.04956 0.50 N4BP1 rs9937623 rs8046716 0.59 T 0.348 0.04956 0.50CDH8 rs4636897 rs11641508 1.00 A 0.023 0.03974 0.15 BEAN rs4247350rs4247350 N/A C 0.174 0.02628 0.40 KIAA0513 rs4783121 rs4783121 N/A A0.087 0.01362 6.76 KIAA0182 rs736845 rs736845 N/A T 0.182 0.04535 0.43PMP22 rs13422 rs230911 0.59 A 0.326 0.03223 0.47 PMP22 rs230938 rs2309110.61 A 0.326 0.03223 0.47 PMP22 rs231018 rs230911 0.75 A 0.326 0.032230.47 PMP22 rs231021 rs230911 0.78 A 0.326 0.03223 0.47 FUSSEL18 rs892583rs7244178 0.68 T 0.217 0.009474 0.37 FUSSEL18 rs892583 rs892583 N/A G0.205 0.04865 0.45 DCC rs12457407 rs11876282 0.65 G 0.591 0.04231 2.02DCC rs1393331 rs17506154 1.00 C 0.587 0.01453 2.30 DCC rs4940251rs17506154 0.53 C 0.587 0.01453 2.30 DCC rs6508145 rs1031062 0.67 G0.065 0.01905 0.25 DCC rs6508235 rs2036415 0.58 G 0.548 0.03016 2.14 DCCrs7506904 rs11876282 0.58 G 0.591 0.04231 2.02 DCC rs8097413 rs105029691.00 C 0.196 0.01433 3.21 DCC rs950278 rs11876282 0.56 G 0.591 0.042312.02 TMEPAI rs427278 rs203386 0.51 C 0.591 0.0107 2.43

Example 3 Novel Markers Associated with Risperidone Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on risperidoneresponse was performed using as described in Example 2 with the PLINK1.03 whole genome analysis toolset developed by Purcell and coworkers(Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). PLINK calculatesP values for the allele-specific chi-squared test and the odds ratio(OR; or relative risk) associated with the minor allele.

Confirmation of SNP Effects on Risperidone Response and Side Effects:

Tables 4 and 5 report the minor allele frequencies, P values, and ORsfor SNPs, in Tables B and C that affect risperidone response and sideeffect rates, respectively. Note in Tables 4 and 5 that haplotype blocksresult in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B. Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 4 and 5.

Tables 4 and 5, provide numerous examples of SNP-based alleles thatpredict altered response to risperidone. For Table 4, ORs of >1.0indicate that the minor SNP allele is associated with greater clinicalimprovement, and ORs of <1.0 indicate that the minor SNP allele isassociated with lesser clinical improvement. For Table 5 ORs of >1.0indicate that the minor SNP allele is associated with an increase instudy ending side effects, and ORs of <1.0 indicate that the minor SNPallele is associated a decrease in study ending side effects.

TABLE 4 Alleles Affecting Positive Response to Risperidone Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Alleleresponders P OR RERE rs12136689 rs10779702 0.76 A 0.266 0.03124 0.49RERE rs8627 rs10779702 0.52 A 0.266 0.03124 0.49 DNM3 rs4382763rs6701929 0.84 C 0.156 0.04448 0.46 RABGAP1L rs6425302 rs1793319 0.59 A0.500 0.02472 2.00 CACNA1E rs199960 rs3856093 0.51 C 0.281 0.04197 0.51CACNA1E rs3856090 rs3856093 1.00 C 0.281 0.04197 0.51 ANK3 rs2393607rs2393602 0.56 C 0.484 0.04133 1.88 PTPN5 rs4345940 rs4757718 0.53 G0.219 0.04081 0.49 SYT13 rs11038382 rs7943596 1.00 C 0.194 0.03562 0.46SYT13 rs2863182 rs7943596 0.84 C 0.194 0.03562 0.46 SYT13 rs4992029rs7943596 0.61 C 0.194 0.03562 0.46 CHFR rs3741494 rs3741494 N/A T 0.1940.0429 2.40 JPH4 rs12897422 rs12897422 N/A A 0.188 0.00592 3.58 DAAM1rs4898983 rs2099636 0.96 A 0.203 0.03748 0.48 NEDD4 rs2303579 rs105188310.51 G 0.266 0.002306 3.31 NEDD4 rs2303580 rs10518831 0.51 G 0.2660.002306 3.31 GRINL1A rs4774275 rs1873995 0.51 G 0.359 0.0403 0.53 Gcom1rs986868 rs11071337 0.59 C 0.609 0.01971 2.05 SLCO3A1 rs2286355rs11630872 0.85 T 0.469 0.03077 1.96 N4BP1 rs1039342 rs2129243 1.00 T0.258 0.03604 0.49 N4BP1 rs1120276 rs2129243 1.00 T 0.258 0.03604 0.49N4BP1 rs1224 rs2129243 1.00 T 0.258 0.03604 0.49 N4BP1 rs2354580rs2129243 0.61 T 0.258 0.03604 0.49 N4BP1 rs3826176 rs2129243 0.61 T0.258 0.03604 0.49 N4BP1 rs9937623 rs2129243 0.96 T 0.258 0.03604 0.49CBLN1 rs11076478 rs12598711 0.89 G 0.422 0.01435 2.19 CBLN1 rs9935379rs12598711 0.72 G 0.422 0.01435 2.19 CDH8 rs1397131 rs9925201 0.76 G0.594 0.02591 1.98 CDH8 rs8057338 rs9925201 0.79 G 0.594 0.02591 1.98CDH8 rs9302540 rs9925201 0.79 G 0.594 0.02591 1.98 CDH8 rs9302540rs9302540 N/A G 0.563 0.04052 1.88 SMAD7 rs736839 rs2337153 0.73 A 0.5630.003133 2.49 DYM rs8096141 rs7239949 0.87 G 0.113 0.04631 3.18 TMEPAIrs427278 rs203386 0.51 C 0.258 0.03803 0.50

TABLE 5 Alleles Affecting Negative Side Effects for Risperidone Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Allelediscontinuers P OR CAMTA1 rs228651 rs11121029 0.51 A 0.000 0.009148 0.00PER3 rs2640909 rs228652 0.70 A 0.542 0.01808 2.77 RP1-21O18.1 rs2073091rs761288 0.69 C 0.542 0.004869 3.34 RP1-21O18.1 rs4661572 rs761288 0.56C 0.542 0.004869 3.34 SLC6A17 rs12133992 rs2784140 0.90 G 0.708 0.04342.54 SLC6A17 rs534276 rs2784140 0.60 G 0.708 0.0434 2.54 KCND3 rs197422rs197412 0.94 C 0.167 0.01199 0.26 DNM3 rs13932 rs9425606 0.75 G 0.5000.00697 3.21 DNM3 rs4382763 rs12410416 1.00 C 0.417 0.008488 3.20 DNM3rs4382763 rs4382763 N/A A 0.375 0.0302 2.68 KCNH1 rs1770213 rs17772640.94 C 0.000 0.01943 0.00 DPH3 rs2245708 rs842252 1.00 A 0.583 0.022542.68 EXOC2 rs2493049 rs12154040 0.54 C 0.667 0.00848 3.21 ANK3 rs1551684rs1551683 1.00 T 0.292 0.007594 3.71 ANK3 rs1551684 rs1551684 N/A A0.250 0.03112 3.04 DEAF1 rs4963145 rs936465 0.53 G 0.182 0.002149 0.20DEAF1 rs6597990 rs10902190 0.58 T 0.083 0.01958 0.20 DEAF1 rs6597996rs936465 0.58 G 0.182 0.002149 0.20 DEAF1 rs936465 rs936465 N/A G 0.1820.002149 0.20 PTPN5 rs4345940 rs7117716 0.97 T 0.583 0.004185 3.42 PTPN5rs7932938 rs7117716 0.54 T 0.583 0.004185 3.42 SLC17A6 rs11026532rs1155331 0.96 T 0.042 0.01523 0.12 SYT13 rs4992029 rs7117240 0.55 C0.625 0.0497 2.37 SYT13 rs8929 rs7117240 0.54 C 0.625 0.0497 2.37RTN4RL2 rs2511986 rs2649667 0.87 T 0.000 0.006313 0.00 KIAA1853rs7297606 rs4075945 1.00 T 0.333 0.0007673 4.88 RIMBP2 rs2277356rs4759462 0.76 T 0.292 0.0369 2.77 NDRG2 rs1243444 rs1243446 0.58 G0.167 0.01347 0.26 NDRG2 rs1243446 rs1243446 N/A G 0.167 0.01347 0.26DAAM1 rs17833769 rs1958180 0.95 G 0.083 0.03279 0.22 DAAM1 rs1958180rs1958180 N/A G 0.083 0.03279 0.22 GPR135 rs10136708 rs1253103 0.54 C0.250 0.04172 0.38 GPR135 rs10138199 rs1253103 0.88 C 0.250 0.04172 0.38GPR135 rs1253181 rs1253103 0.71 C 0.250 0.04172 0.38 GPR135 rs17255731rs1253103 0.57 C 0.250 0.04172 0.38 GPR135 rs4898989 rs1253103 0.88 C0.250 0.04172 0.38 GPR135 rs9323348 rs1253103 0.88 C 0.250 0.04172 0.38HERC2 rs11074322 rs6497272 1.00 G 0.083 0.003758 15.55 HERC2 rs1635168rs6497292 0.87 G 0.208 0.002843 5.40 HERC2 rs2238289 rs6497292 0.51 G0.208 0.002843 5.40 HERC2 rs7495174 rs6497292 0.58 G 0.208 0.002843 5.40UNC13C rs16974691 rs16974712 0.96 T 0.042 0.04931 0.16 SV2B rs1117388rs1117387 1.00 T 0.042 0.03508 0.15 SV2B rs3743444 rs1117387 0.57 T0.042 0.03508 0.15 SLCO3A1 rs2176452 rs8027160 0.58 G 0.500 0.01784 2.78IGF1R rs11247380 rs3743258 0.93 A 0.500 0.02156 2.70 IGF1R rs1879613rs3743258 0.51 A 0.500 0.02156 2.70 CBLN1 rs3743777 rs8052939 0.89 G0.167 0.03498 3.62 CDH8 rs11075445 rs13336134 0.80 C 0.583 0.02155 2.72CDH8 rs1369918 rs13336134 0.80 C 0.583 0.02155 2.72 CDH8 rs1978796rs13336134 0.80 C 0.583 0.02155 2.72 CDH8 rs6498807 rs13336134 1.00 C0.583 0.02155 2.72 CDH8 rs9939991 rs13336134 0.55 C 0.583 0.02155 2.72CDH11 rs35144 rs40115 1.00 T 0.500 0.01784 2.78 CDH11 rs35148 rs401150.68 T 0.500 0.01784 2.78 CDH11 rs35186 rs40115 0.56 T 0.500 0.017842.78 CDH11 rs35195 rs35195 N/A A 0.500 0.01938 2.74 CDH11 rs35144rs35144 N/A C 0.500 0.02156 2.70 DCC rs1393331 rs1502229 0.84 G 0.1360.01594 0.24 DCC rs4940251 rs1502229 0.59 G 0.136 0.01594 0.24 DCCrs6508235 rs1502229 0.58 G 0.136 0.01594 0.24

Example 4 Novel Markers Associated with Quetiapine Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on quetiapineresponse was performed using as described in Example 2 with the PLINK1.03 whole genome analysis toolset developed by Purcell and coworkers(Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). PLINK calculatesP values for the allele-specific chi-squared test and the odds ratio(OR; or relative risk) associated with the minor allele.

Confirmation of SNP Effects on Quetiapine Response and Side Effects:

Tables 6 and 7 report the minor allele frequencies, P values, and ORsfor SNPs, in Tables B and C that affect quetiapine response and sideeffect rates, respectively. Note in Tables 6 and 7 that haplotype blocksresult in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B. Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 6 and 7.

Tables 6 and 7, provide numerous examples of SNP-based alleles thatpredict altered response to quetiapine. For Table 6, ORs of >1.0indicate that the minor SNP allele is associated with greater clinicalimprovement, and ORs of <1.0 indicate that the minor SNP allele isassociated with lesser clinical improvement. For Table 7 ORs of >1.0indicate that the minor SNP allele is associated with an increase instudy ending side effects, and ORs of <1.0 indicate that the minor SNPallele is associated a decrease in study ending side effects.

TABLE 6 Alleles Affecting Positive Response to Quetiapine Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Alleleresponders P OR RP1-21O18.1 rs7546786 rs7546786 N/A C 0.340 0.03888 2.12CACNA1E rs638132 rs678643 0.86 G 0.300 0.04268 2.14 CAMK1G rs2356933rs6683256 1.00 T 0.208 0.02384 0.42 EXOC2 rs2294660 rs1150856 0.55 C0.280 0.03354 2.28 EXOC2 rs998777 rs17135931 0.66 A 0.300 0.0313 2.26YPEL4 rs1798177 rs1798173 0.84 T 0.280 0.01513 0.42 YPEL4 rs7947357rs1798173 0.84 T 0.280 0.01513 0.42 CTNND1 rs10896644 rs1786438 0.97 T0.313 0.007608 0.40 CTNND1 rs11570176 rs1786438 0.97 T 0.313 0.0076080.40 CTNND1 rs2156638 rs1786438 1.00 T 0.313 0.007608 0.40 CTNND1rs652908 rs1786438 1.00 T 0.313 0.007608 0.40 CTNND1 rs708228 rs5768591.00 A 0.458 0.01184 2.36 KIAA1853 rs7297606 rs4075945 1.00 T 0.2000.009895 3.30 STX2 rs1236 rs10848205 1.00 T 0.580 0.02392 2.11 STX2rs4759517 rs10848205 0.81 T 0.580 0.02392 2.11 STX2 rs6486600 rs108482050.79 T 0.580 0.02392 2.11 STX2 rs6486602 rs10848205 0.81 T 0.580 0.023922.11 DACT1 rs464582 rs464582 N/A C 0.520 0.03106 2.04 DAAM1 rs10143918rs10873113 0.58 T 0.280 0.0335 2.29 DAAM1 rs11626926 rs4901921 0.85 T0.563 0.01108 2.36 DAAM1 rs12147707 rs10873113 0.86 T 0.280 0.0335 2.29DAAM1 rs17095965 rs10873113 0.86 T 0.280 0.0335 2.29 DAAM1 rs4127823rs4901921 0.60 T 0.563 0.01108 2.36 GPR135 rs10136708 rs1253103 0.54 C0.280 0.04103 0.49 GPR135 rs10138199 rs1253103 0.88 C 0.280 0.04103 0.49GPR135 rs1253181 rs1253103 0.71 C 0.280 0.04103 0.49 GPR135 rs17255731rs1253103 0.57 C 0.280 0.04103 0.49 GPR135 rs4898989 rs1253103 0.88 C0.280 0.04103 0.49 GPR135 rs9323348 rs1253103 0.88 C 0.280 0.04103 0.49RTN1 rs10145080 rs17731838 0.65 T 0.100 0.008147 0.28 RTN1 rs12717467rs17731838 0.52 T 0.100 0.008147 0.28 RTN1 rs17310036 rs17731838 0.81 T0.100 0.008147 0.28 EML1 rs2273704 rs12590861 0.61 C 0.500 0.001846 2.84EML1 rs7143905 rs12590861 0.70 C 0.500 0.001846 2.84 EML1 rs2273704rs2273704 N/A C 0.520 0.01052 2.34 EVL rs3206354 rs12431406 0.58 C 0.1400.007758 4.53 UNC13C rs9920139 rs1961635 0.55 T 0.200 0.03866 2.52UNC13C rs9920150 rs1961635 0.61 T 0.200 0.03866 2.52 Gcom1 rs986868rs11071337 0.59 C 0.640 0.003757 2.64 AKAP13 rs1053992 rs12440599 0.61 T0.460 0.04784 1.94 AKAP13 rs11073502 rs2291048 0.53 A 0.174 0.03896 0.42AKAP13 rs2061821 rs12440599 0.96 T 0.460 0.04784 1.94 AKAP13 rs2061822rs12440599 0.89 T 0.460 0.04784 1.94 AKAP13 rs2061824 rs12440599 0.96 T0.460 0.04784 1.94 AKAP13 rs338523 rs12440599 0.96 T 0.460 0.04784 1.94AKAP13 rs4075254 rs12440599 0.96 T 0.460 0.04784 1.94 AKAP13 rs4075256rs12440599 0.96 T 0.460 0.04784 1.94 AKAP13 rs4842895 rs12440599 0.76 T0.460 0.04784 1.94 AKAP13 rs4843074 rs12440599 0.96 T 0.460 0.04784 1.94AKAP13 rs4843075 rs12440599 0.96 T 0.460 0.04784 1.94 AKAP13 rs7162168rs12440599 0.96 T 0.460 0.04784 1.94 SV2B rs1075840 rs1079535 0.87 A0.480 0.02175 2.15 SV2B rs2301665 rs1079535 0.74 A 0.480 0.02175 2.15SV2B rs8027498 rs1079535 0.60 A 0.480 0.02175 2.15 RGMA rs13167rs11074130 0.59 T 0.180 0.003617 4.30 IGF1R rs11247380 rs1521481 0.73 C0.240 0.02095 0.43 IGF1R rs2684808 rs951715 0.51 G 0.260 0.02238 0.44IGF1R rs8030950 rs1879612 0.66 C 0.188 0.02051 0.40 BEAN rs4247350rs11645280 0.61 G 0.417 0.02122 2.22 FUSSEL18 rs892583 rs2164098 0.95 G0.420 0.01515 2.30 FUSSEL18 rs892583 rs892583 N/A G 0.391 0.04015 2.08KIAA0427 rs2175565 rs12456253 0.68 G 0.220 0.03731 0.46 KIAA0427rs4939813 rs1994559 0.53 A 0.240 0.006482 3.18 KIAA0427 rs937021rs12458062 0.52 T 0.600 0.03871 1.98 DCC rs1247407 rs7506909 0.93 A0.520 0.01922 2.17 DCC rs1393331 rs17504520 0.78 G 0.587 0.02781 2.12DCC rs2229080 rs9966074 0.60 T 0.340 0.01745 0.45 DCC rs4940251rs7506909 0.67 A 0.520 0.01922 2.17 DCC rs6508145 rs1454731 0.82 C 0.3200.01176 2.57 DCC rs6508235 rs10515959 0.77 T 0.340 0.03565 2.13 DCCrs7506904 rs7506909 0.83 A 0.520 0.01922 2.17 DCC rs950278 rs99660740.87 T 0.340 0.01745 0.45

TABLE 7 Alleles Affecting Negative Side Effects for Quetiapine Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Allelediscontinuers P OR CAMTA1 rs845197 rs845265 0.91 T 0.095 0.02848 0.31RERE rs7530745 rs6577499 1.00 G 0.273 0.03893 0.46 RERE rs7554486rs6577499 0.65 G 0.273 0.03893 0.46 SLC16A4 rs10857820 rs3768458 0.65 T0.318 0.04016 0.48 SLC16A4 rs1334882 rs3768458 1.00 T 0.318 0.04016 0.48KCNA10 rs3768456 rs7543509 1.00 G 0.182 0.0001722 8.11 CACNA1Ers17494681 rs17494681 N/A T 0.296 0.0268 2.40 CACNA1E rs3856090rs7534913 0.50 G 0.381 0.04817 0.50 KCNH1 rs4620600 rs4951495 0.79 A0.068 0.01863 0.25 ANK3 rs2393596 rs10761451 0.78 G 0.159 0.04472 0.41DEAF1 rs7109335 rs7123677 0.84 T 0.227 0.03893 2.46 DEAF1 rs7121608rs7123677 0.92 T 0.227 0.03893 2.46 DEAF1 rs7935419 rs7123677 0.92 T0.227 0.03893 2.46 USH1C rs10766408 rs2041032 0.51 T 0.568 0.01695 2.27USH1C rs2041027 rs2041032 0.78 T 0.568 0.01695 2.27 USH1C rs2237957rs2041032 0.69 T 0.568 0.01695 2.27 KCNC1 rs10766434 rs2299637 0.66 A0.455 0.01364 2.37 KCNC1 rs2299637 rs2299637 N/A A 0.455 0.01364 2.37KCNC1 rs757514 rs2299637 0.66 A 0.455 0.01364 2.37 NAV2 rs10833202rs11025328 0.61 A 0.727 0.001805 3.13 SLC17A6 rs11026523 rs1562445 0.79A 0.068 0.008164 0.22 SLC17A6 rs1155821 rs1562445 0.96 A 0.068 0.0081640.22 SLC17A6 rs2078352 rs1562445 1.00 A 0.068 0.008164 0.22 SLC17A6rs2246710 rs1562445 1.00 A 0.068 0.008164 0.22 SLC17A6 rs2078352rs2078352 N/A T 0.068 0.01127 0.23 LRRC4C rs10837367 rs10501225 0.69 A0.023 0.03099 0.14 RTN4RL2 rs2511986 rs2649667 0.87 T 0.409 0.04498 2.04KIAA1853 rs7297606 rs4075945 1.00 T 0.023 0.04399 0.16 CHFR rs2306536rs11147101 1.00 G 0.091 0.04245 0.34 CHFR rs4758954 rs11147101 1.00 G0.091 0.04245 0.34 GPR135 rs10136708 rs1253103 0.54 C 0.546 0.02737 2.13GPR135 rs10138199 rs2774052 0.72 A 0.614 0.01223 2.38 GPR135 rs1253181rs2774052 0.89 A 0.614 0.01223 2.38 GPR135 rs17255731 rs2774052 0.70 A0.614 0.01223 2.38 GPR135 rs4898989 rs2774052 0.72 A 0.614 0.01223 2.38GPR135 rs9323348 rs2774052 0.72 A 0.614 0.01223 2.38 EML1 rs2273704rs12590861 0.61 C 0.182 0.02262 0.39 EML1 rs7143905 rs12590861 0.70 C0.182 0.02262 0.39 EVL rs1190954 rs1190967 0.96 G 0.182 0.02583 0.40 EVLrs1190956 rs1190967 0.60 G 0.182 0.02583 0.40 EVL rs1190974 rs11909670.96 G 0.182 0.02583 0.40 WDR25 rs10873518 rs7492607 0.97 C 0.5230.01011 2.43 UNC13C rs11856476 rs8023723 0.53 G 0.477 0.04506 2.00UNC13C rs12914912 rs8023723 0.86 G 0.477 0.04506 2.00 UNC13C rs4776216rs8023723 1.00 G 0.477 0.04506 2.00 NEDD4 rs17238461 rs2175104 0.53 A0.048 0.04132 0.24 AKAP13 rs338556 rs870689 0.91 A 0.136 0.009364 4.58KLHL25 rs2430838 rs870689 1.00 A 0.136 0.009364 4.58 KLHL25 rs2430838rs2430838 N/A T 0.114 0.03635 3.67 SLCO3A1 rs2176452 rs8027160 0.58 G0.136 0.01379 0.33 NETO2 rs11859615 rs9928466 0.85 C 0.000 0.03539 0.00NETO2 rs16952126 rs9928466 0.85 C 0.000 0.03539 0.00 NETO2 rs7184206rs9928466 1.00 C 0.000 0.03539 0.00 NETO2 rs9923731 rs9928466 0.85 C0.000 0.03539 0.00 ZNF423 rs12924119 rs2883977 0.51 C 0.341 0.0058382.86 NDRG4 rs13333449 rs16960170 0.80 C 0.341 0.03824 2.18 NDRG4rs7202037 rs16960170 0.67 C 0.341 0.03824 2.18 CDH8 rs1397131 rs169641640.90 T 0.523 0.02822 2.13 CDH8 rs8057338 rs16964164 0.93 T 0.523 0.028222.13 CDH8 rs9302540 rs16964164 0.93 T 0.523 0.02822 2.13 CDH11 rs35144rs40115 1.00 T 0.477 0.03109 2.12 CDH11 rs35148 rs40115 0.68 T 0.4770.03109 2.12 CDH11 rs35186 rs40115 0.56 T 0.477 0.03109 2.12 CDH11rs35195 rs35195 N/A A 0.477 0.04506 2.00 CDH11 rs35186 rs35186 N/A T0.619 0.03313 2.13 BEAN rs4247350 rs1063438 0.59 A 0.182 0.006152 0.32KIAA0427 rs2306514 rs2306514 N/A G 0.500 0.02294 2.19 KIAA0427 rs752151rs2337099 0.83 G 0.136 0.003807 5.76 KIAA0427 rs937021 rs12458062 0.52 T0.341 0.044 0.49 TMEPAI rs427278 rs203386 0.51 C 0.250 0.02943 0.44

Example 5 Novel Markers Associated with Perphenazine Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on perphenazineresponse was performed using as described in Example 2 with the PLINK1.03 whole genome analysis toolset developed by Purcell and coworkers(Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). PLINK calculatesP values for the allele-specific chi-squared test and the odds ratio(OR; or relative risk) associated with the minor allele.

Confirmation of SNP Effects on Perphenazine Response and Side Effects:

Tables 8 and 9 report the minor allele frequencies, P values, and ORsfor SNPs, in Tables B and C that affect perphenazine response and sideeffect rates, respectively. Note in Tables 8 and 9 that haplotype blocksresult in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 8 and 9.

Tables 8 and 9, provide numerous examples of SNP-based alleles thatpredict altered response to perphenazine. For Table 8, ORs of >1.0indicate that the minor SNP allele is associated with greater clinicalimprovement, and ORs of <1.0 indicate that the minor SNP allele isassociated with lesser clinical improvement. For Table 9 ORs of >1.0indicate that the minor SNP allele is associated with an increase instudy ending side effects, and ORs of <1.0 indicate that the minor SNPallele is associated a decrease in study ending side effects.

TABLE 8 Alleles Affecting Positive Response to Perphenazine Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r² Alleleresponders P OR CAMTA1 rs6577393 rs6657847 0.51 T 0.391 0.04251 2.04CAMTA1 rs6577401 rs6698901 0.59 G 0.641 0.03272 2.03 RP1-21O18.1rs4661572 rs4501834 0.60 C 0.242 0.02391 2.68 CACNA1E rs199960 rs19536900.81 A 0.422 0.04061 2.01 CAMK1G rs9430004 rs9430004 N/A T 0.563 0.012622.27 KCNH1 rs1393026 rs7529770 0.52 G 0.323 0.01484 0.44 KCNH1 rs1770220rs1777256 1.00 A 0.266 0.007082 0.39 ANK3 rs3750800 rs3750800 N/A A0.281 0.03529 0.48 TOLLIP rs3168046 rs2672812 0.85 G 0.375 0.03841 0.51TOLLIP rs3750920 rs2672812 0.85 G 0.375 0.03841 0.51 HCCA2 rs7396514rs10734456 0.55 C 0.141 0.03102 0.41 DUSP8 rs10734456 rs10734456 N/A C0.141 0.03102 0.41 DUSP8 rs902224 rs10734456 0.74 C 0.141 0.03102 0.41KCNC1 rs10766434 rs10766426 0.78 G 0.484 0.01735 2.21 KCNC1 rs2299637rs10766426 0.56 G 0.484 0.01735 2.21 KCNC1 rs757514 rs10766426 0.78 G0.484 0.01735 2.21 SERGEF rs172424 rs2299628 0.65 G 0.281 0.02554 0.46SERGEF rs211130 rs2299628 0.65 G 0.281 0.02554 0.46 SERGEF rs211137rs2299628 0.65 G 0.281 0.02554 0.46 SERGEF rs211146 rs2299628 1.00 G0.281 0.02554 0.46 SERGEF rs2283233 rs2299628 1.00 G 0.281 0.02554 0.46SERGEF rs1528 rs1528 N/A C 0.188 0.007483 4.11 SERGEF rs2283233rs2283233 N/A C 0.274 0.02958 0.47 NAV2 rs2585788 rs2625312 0.84 A 0.2030.04449 0.47 SLC17A6 rs1979072 rs11026546 1.00 A 0.250 0.009104 3.15SLC17A6 rs1979073 rs11026546 1.00 A 0.250 0.009104 3.15 SLC17A6rs2593644 rs11026546 0.88 A 0.250 0.009104 3.15 SLC17A6 rs764021rs721840 0.97 C 0.242 0.02368 0.44 PHACS rs3107275 rs3134907 0.79 C0.203 0.02318 0.43 KIAA1853 rs1568923 rs10851061 0.58 G 0.188 0.035280.45 KIAA1545 rs10870551 rs4418881 1.00 G 0.234 0.0243 0.44 KIAA1545rs4883513 rs4883513 N/A T 0.233 0.01119 0.40 RTN1 rs17255975 rs18847370.75 G 0.234 0.01716 2.89 UNC13C rs11856476 rs8024165 0.84 T 0.4380.01674 2.27 UNC13C rs12914912 rs8024165 0.63 T 0.438 0.01674 2.27UNC13C rs4776216 rs8024165 0.52 T 0.438 0.01674 2.27 UNC13C rs9920139rs9920150 0.91 G 0.047 0.04211 0.28 UNC13C rs9920150 rs9920150 N/A G0.047 0.04211 0.28 NEDD4 rs1509408 rs1509408 N/A C 0.281 0.03119 2.38GRINL1A rs16977631 rs11638184 0.52 A 0.063 0.004306 0.22 GCOM1 rs2733619rs2733619 N/A C 0.016 0.04231 0.15 AKAP13 rs338556 rs8025135 0.71 G0.297 0.0149 2.63 KLHL25 rs2430838 rs8025135 0.64 G 0.297 0.0149 2.63SLCO3A1 rs2286355 rs11630872 0.85 T 0.422 0.01222 2.39 SLCO3A1 rs6496893rs11638063 1.00 A 0.047 0.04211 0.28 CBLN1 rs11076478 rs893175 0.53 C0.484 0.007589 2.46 CBLN1 rs3743777 rs8052939 0.89 G 0.094 0.01269 9.62CBLN1 rs9935379 rs893175 0.69 C 0.484 0.007589 2.46 CDH11 rs35144rs35164 0.68 T 0.145 0.04592 0.43 CDH11 rs35148 rs35164 1.00 T 0.1450.04592 0.43 BEAN rs11644279 rs11075635 0.59 C 0.266 0.02787 2.47 COX10rs4792434 rs8077302 0.55 G 0.597 0.01289 2.28 COX10 rs8077302 rs8077302N/A G 0.597 0.01289 2.28 KATNAL2 rs2247221 rs4986203 0.53 A 0.4680.04996 1.95 KATNAL2 rs2571030 rs4986203 0.53 A 0.468 0.04996 1.95KATNAL2 rs9961383 rs4986203 0.53 A 0.468 0.04996 1.95 FUSSEL18rs10502880 rs11082575 0.55 G 0.339 0.01242 0.43 FUSSEL18 rs17785419rs11082575 0.55 G 0.339 0.01242 0.43 FUSSEL18 rs2668771 rs9965170 0.56 A0.406 0.02724 0.49 FUSSEL18 rs7236105 rs9965170 0.88 A 0.406 0.027240.49 DCC rs12457407 rs9949949 0.83 A 0.453 0.03236 2.06 DCC rs1893572rs7228674 0.77 T 0.156 0.03404 0.42 DCC rs4940251 rs9949949 0.82 A 0.4530.03236 2.06 DCC rs7506904 rs9949949 0.93 A 0.453 0.03236 2.06 BMP7rs230198 rs230191 0.97 T 0.406 0.02724 0.49 TMEPAI rs6015068 rs6015068N/A T 0.484 0.01161 2.33

TABLE 9 Alleles Affecting Negative Side Effects for Perphenazine TestSNP Frequency Gene Table in linkage in Name B SNP disequilibrium r²Allele discontinuers P OR CAMTA1 rs12070592 rs9434833 1.00 T 0.3330.02671 2.92 SLC6A17 rs924181 rs1571346 0.64 G 0.583 0.03113 2.59 KCNC4rs11578913 rs11578913 N/A A 0.167 0.04276 0.33 SLC16A4 rs10857820rs3768458 0.65 T 0.625 0.04343 2.47 SLC16A4 rs1334882 rs3768458 1.00 T0.625 0.04343 2.47 CAMK1G rs11119315 rs11119315 N/A A 0.292 0.02755 3.04CAMK1G rs6690557 rs713075 0.80 A 0.500 0.02324 2.72 KCNH1 rs1770220rs10863854 0.65 T 0.292 0.04383 0.39 TOLLIP rs3168046 rs2014486 0.85 A0.667 0.0345 2.62 TOLLIP rs3750920 rs2014486 0.85 A 0.667 0.0345 2.62OTOG rs2041028 rs734640 0.55 G 0.083 0.03774 0.23 OTOG rs2355466rs734640 0.55 G 0.083 0.03774 0.23 OTOG rs4757548 rs734640 0.50 G 0.0830.03774 0.23 OTOG rs7111528 rs734640 0.55 G 0.083 0.03774 0.23 SERGEFrs172424 rs4141243 0.65 C 0.625 0.009037 3.19 SERGEF rs211130 rs41412430.65 C 0.625 0.009037 3.19 SERGEF rs211137 rs4141243 0.65 C 0.6250.009037 3.19 SERGEF rs211146 rs4141243 1.00 C 0.625 0.009037 3.19SERGEF rs2283233 rs4141243 1.00 C 0.625 0.009037 3.19 SERGEF rs2283233rs2283233 N/A C 0.583 0.02427 2.71 PTPN5 rs4274187 rs4075664 0.67 C0.667 0.04808 2.47 HSD17B12 rs1061810 rs10768983 0.87 G 0.455 0.030892.72 HSD17B12 rs4755744 rs10768983 1.00 G 0.455 0.03089 2.72 ZFP91-CNTFrs1938596 rs2509920 0.97 C 0.625 0.04343 2.47 ZFP91-CNTF rs4319530rs2509920 0.90 C 0.625 0.04343 2.47 KIAA1545 rs10870551 rs4418881 1.00 G0.542 0.01977 2.80 EML1 rs2250718 rs3783322 0.70 G 0.250 0.02801 0.34UNC13C rs11639005 rs7163424 0.62 T 0.167 0.03824 0.32 UNC13C rs12914912rs12912762 0.71 A 0.591 0.0436 2.53 UNC13C rs4776216 rs12912762 0.77 A0.591 0.0436 2.53 UNC13C rs9302181 rs7163424 0.64 T 0.167 0.03824 0.32AKAP13 rs16977252 rs17623915 0.75 C 0.375 0.005111 3.73 KLHL25 rs2554rs17623915 0.62 C 0.375 0.005111 3.73 SLCO3A1 rs12912997 rs12912997 N/AG 0.542 0.02862 2.62 IGF1R rs11247380 rs7165181 0.55 G 0.292 0.045862.74 IGF1R rs1879613 rs7165181 0.96 G 0.292 0.04586 2.74 CDH8 rs11075445rs11075445 N/A G 0.208 0.02023 0.31 CDH8 rs1369918 rs11075445 1.00 G0.208 0.02023 0.31 CDH8 rs1978796 rs11075445 1.00 G 0.208 0.02023 0.31CDH8 rs6498807 rs11075445 0.80 G 0.208 0.02023 0.31 CDH8 rs9939991rs4784163 0.55 G 0.167 0.04276 0.33 KIAA0513 rs3794684 rs3794682 0.69 A0.250 0.03871 0.36 KIAA0513 rs4783121 rs715707 1.00 A 0.125 0.01543 6.24KIAA0513 rs4783121 rs4783121 N/A A 0.125 0.03696 4.64 COX10 rs2302107rs1003060 0.89 T 0.042 0.0156 0.12 FUSSEL18 rs10502880 rs17785419 1.00 A0.292 0.02612 0.35 FUSSEL18 rs17785419 rs17785419 N/A A 0.292 0.026120.35 FUSSEL18 rs2668771 rs17785419 0.54 A 0.292 0.02612 0.35 FUSSEL18rs7236105 rs17785419 0.85 A 0.292 0.02612 0.35 FUSSEL18 rs892583rs892583 N/A G 0.500 0.001787 3.96 DYM rs8096141 rs16950298 0.61 C 0.1670.04251 3.63 DCC rs6508145 rs1031062 0.67 G 0.250 0.02271 3.39

Example 6 Novel Markers Associated with Ziprasidone Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on ziprasidoneresponse was performed using as described in Example 2 with the PLINK1.03 whole genome analysis toolset developed by Purcell and coworkers(Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). PLINK calculatesP values for the allele-specific chi-squared test and the odds ratio(OR; or relative risk) associated with the minor allele.

Confirmation of SNP Effects on Ziprasidone Response and Side Effects:

Tables 10 and 11 report the minor allele frequencies, P values, and ORsfor SNPs, in Tables B and C that affect ziprasidone response and sideeffect rates, respectively. Note in Tables 10 and 11 that haplotypeblocks result in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 10 and 11.

Tables 10 and 11, provide numerous examples of SNP-based alleles thatpredict altered response to ziprasidone. For Table 10, ORs of >1.0indicate that the minor SNP allele is associated with greater clinicalimprovement, and ORs of <1.0 indicate that the minor SNP allele isassociated with lesser clinical improvement. For Table 11 ORs of >1.0indicate that the minor SNP allele is associated with an increase instudy ending side effects, and ORs of <1.0 indicate that the minor SNPallele is associated a decrease in study ending side effects.

TABLE 10 Alleles Affecting Positive Response to Ziprasidone Test SNPFrequency Gene Table in linkage in Name B SNP disequilibrium r2 Alleleresponders P OR RP1-21O18.1 rs2073091 rs761288 0.69 C 0.235 0.0481 0.40RP1-21O18.1 rs4661572 rs761288 0.56 C 0.235 0.0481 0.40 KCND3 rs4838924rs1373291 0.86 T 0.147 0.03358 0.32 RABGAP1L rs16847624 rs10912854 0.84C 0.125 0.03253 0.29 RABGAP1L rs6425302 rs10912854 0.96 C 0.125 0.032530.29 CACNA1E rs199960 rs3856093 0.51 C 0.206 0.0147 0.31 CACNA1Ers3856090 rs3856093 1.00 C 0.206 0.0147 0.31 CACNA1E rs506947 rs168574570.93 G 0.219 0.009356 5.69 DPH3 rs2245721 rs842264 0.57 T 0.618 0.033732.49 DPH3 rs842257 rs842264 0.57 T 0.618 0.03373 2.49 DPH3 rs859703rs842264 0.57 T 0.618 0.03373 2.49 EXOC2 rs2294660 rs2073008 0.54 T0.000 0.008039 0.00 EXOC2 rs998777 rs2073008 0.74 T 0.000 0.008039 0.00BRSK2 rs1554857 rs7396009 0.81 T 0.529 0.04022 2.41 HCCA2 rs7396514rs7396009 1.00 T 0.529 0.04022 2.41 HCCA2 rs7945160 rs7396009 0.55 T0.529 0.04022 2.41 HCCA2 rs9440 rs7396009 0.55 T 0.529 0.04022 2.41DUSP8 rs10734456 rs7396009 0.55 T 0.529 0.04022 2.41 DUSP8 rs902224rs7396009 0.81 T 0.529 0.04022 2.41 KCNQ1 rs231348 rs231348 N/A T 0.2940.003769 5.08 OTOG rs11024357 rs11024357 N/A C 0.353 0.03601 2.73 OTOGrs11024358 rs11024357 1.00 C 0.353 0.03601 2.73 PTPN5 rs4757707rs11024786 0.64 T 0.471 0.01003 3.18 NAV2 rs7125647 rs2119981 0.61 A0.618 0.01558 2.83 SLC6A5 rs2001982 rs7950354 0.57 C 0.147 0.02376 0.30LRRC4C rs2953310 rs2953310 N/A C 0.235 0.01582 0.33 HSD17B12 rs1061810rs17596617 0.54 T 0.147 0.02376 0.30 HSD17B12 rs10838160 rs938942 0.59 T0.618 0.04616 2.36 HSD17B12 rs3802891 rs938942 0.59 T 0.618 0.04616 2.36HSD17B12 rs4755744 rs17596617 0.65 T 0.147 0.02376 0.30 ZFP91-CNTFrs1938596 rs2509920 0.97 C 0.559 0.04351 2.37 ZFP91-CNTF rs4319530rs2509920 0.90 C 0.559 0.04351 2.37 DTX4 rs1048444 rs544864 0.55 T 0.1470.03358 0.32 DTX4 rs2211912 rs2211912 N/A A 0.353 0.03477 0.40 DTX4rs3847 rs544864 0.55 T 0.147 0.03358 0.32 DTX4 rs5029315 rs2211912 1.00A 0.353 0.03477 0.40 DTX4 rs544864 rs544864 N/A T 0.147 0.03358 0.32DTX4 rs621162 rs544864 1.00 T 0.147 0.03358 0.32 DTX4 rs656163 rs22119120.88 A 0.353 0.03477 0.40 TTC5 rs10873395 rs8022565 0.77 C 0.441 0.027022.68 TTC5 rs2318864 rs8022565 0.73 C 0.441 0.02702 2.68 TTC5 rs3742945rs8022565 0.73 C 0.441 0.02702 2.68 TTC5 rs2318864 rs2318864 N/A G 0.4410.04178 2.47 TEP1 rs1713449 rs1760909 0.96 T 0.059 0.01999 0.19 TEP1rs7150689 rs1760909 0.87 T 0.059 0.01999 0.19 TEP1 rs938886 rs17609091.00 T 0.059 0.01999 0.19 TEP1 rs938887 rs1760909 0.67 T 0.059 0.019990.19 TEP1 rs1713449 rs1713449 N/A T 0.059 0.02358 0.20 DAAM1 rs1252989rs1957409 0.94 A 0.250 0.01917 0.33 DAAM1 rs1253005 rs1957409 1.00 A0.250 0.01917 0.33 DAAM1 rs1268579 rs2053298 1.00 T 0.441 0.04178 2.47DAAM1 rs4901909 rs1957409 0.62 A 0.250 0.01917 0.33 DAAM1 rs8022614rs1957409 0.71 A 0.250 0.01917 0.33 DAAM1 rs941884 rs1957409 0.72 A0.250 0.01917 0.33 EML1 rs11160553 rs8013843 0.71 T 0.059 0.0113 0.17EML1 rs11160563 rs8020741 0.68 T 0.235 0.02281 0.35 EML1 rs12433613rs8013843 0.60 T 0.059 0.0113 0.17 EML1 rs6575751 rs8013843 0.71 T 0.0590.0113 0.17 WDR25 rs10873518 rs11160589 1.00 A 0.529 0.03593 2.48 UNC13Crs12910912 rs12910912 N/A G 0.382 0.001068 5.22 ADAM10 rs4775086rs7161889 0.55 C 0.382 0.02825 2.79 ADAM10 rs514049 rs7161889 0.70 C0.382 0.02825 2.79 ADAM10 rs653765 rs7161889 0.79 C 0.382 0.02825 2.79AKAP13 rs2291049 rs10520596 0.59 G 0.206 0.0113 5.44 AKAP13 rs338556rs8025135 0.71 G 0.059 0.02358 0.20 KLHL25 rs2430838 rs8025135 0.64 G0.059 0.02358 0.20 KLHL25 rs2554 rs10520595 0.50 T 0.353 0.02633 2.95SV2B rs11630131 rs6496778 0.55 G 0.441 0.01303 3.10 SV2B rs2073967rs6496778 0.87 G 0.441 0.01303 3.10 IGF1R rs11247380 rs4966036 0.55 C0.265 0.02113 3.60 IGF1R rs1879613 rs4966036 0.96 C 0.265 0.02113 3.60IGF1R rs8030950 rs1879612 0.66 C 0.559 0.005 3.38 CBLN1 rs11076478rs1469906 0.72 A 0.206 0.004634 0.26 CBLN1 rs9935379 rs1469906 0.90 A0.206 0.004634 0.26 CBLN1 rs9935379 rs9935379 N/A G 0.206 0.02119 0.33CDH8 rs11075445 rs11075445 N/A G 0.559 0.02987 2.53 CDH8 rs1369918rs11075445 1.00 G 0.559 0.02987 2.53 CDH8 rs1978796 rs11075445 1.00 G0.559 0.02987 2.53 CDH8 rs6498807 rs1397126 0.51 G 0.281 0.007855 4.62CDH8 rs9939991 rs6498806 0.65 A 0.294 0.004701 4.92 CDH11 rs35144rs4967886 0.65 A 0.265 0.007512 0.30 CDH11 rs35148 rs35164 1.00 T 0.1770.02306 0.32 CDH11 rs35186 rs35216 0.56 G 0.250 0.03882 0.38 KIAA0513rs12597135 rs8063083 0.53 C 0.559 0.04351 2.37 KIAA0513 rs3751756rs8063083 0.60 C 0.559 0.04351 2.37 KIAA0182 rs3815794 rs1053328 0.73 T0.382 0.04528 2.52 FUSSEL18 rs892583 rs11877471 0.68 G 0.441 0.041782.47 KIAA0427 rs4939813 rs9959212 0.66 A 0.294 0.03491 0.39 DCCrs1431748 rs7504750 0.63 C 0.412 0.03518 2.60 TMEPAI rs427278 rs2033860.51 C 0.294 0.01685 0.35

TABLE 11 Alleles Affecting Negative Side Effects for Ziprasidone TestSNP Frequency Gene Table in linkage in Name B SNP disequilibrium r²Allele discontinuers P OR RERE rs3753275 rs4581300 0.72 T 0.292 0.014044.06 SLC6A17 rs1010892 rs17671169 0.70 A 0.708 0.02545 3.02 SLC6A17rs6689641 rs17671169 0.82 A 0.708 0.02545 3.02 SLC6A17 rs877068rs17671169 0.60 A 0.708 0.02545 3.02 SLC6A17 rs924181 rs17671169 0.53 A0.708 0.02545 3.02 DNM3 rs10752946 rs9425598 1.00 A 0.583 0.01857 3.03CACNA1E rs199960 rs3856093 0.51 C 0.542 0.04571 2.56 CACNA1E rs3856090rs3856093 1.00 C 0.542 0.04571 2.56 KCNH1 rs11119658 rs1875438 0.59 C0.292 0.04465 0.37 KCNH1 rs1393026 rs7529770 0.52 G 0.625 0.01287 3.27KCNH1 rs1501569 rs1501555 0.56 G 0.667 0.01802 3.14 OTOG rs2073582rs972676 0.71 A 0.250 0.04192 0.35 NAV2 rs1372989 rs1982265 0.54 G 0.0000.02984 0.00 SLC6A5 rs2001982 rs7950354 0.57 C 0.458 0.0371 2.73 SYT13rs4992029 rs7117240 0.55 C 0.542 0.03343 2.72 SYT13 rs8929 rs71172400.54 C 0.542 0.03343 2.72 CHFR rs2306536 rs4758911 0.94 C 0.458 0.0051393.97 CHFR rs4758954 rs4758911 0.94 C 0.458 0.005139 3.97 RTN1 rs17255975rs1884737 0.75 G 0.333 0.04006 2.96 UNC13C rs11639005 rs8025195 0.81 G0.208 0.04687 0.34 UNC13C rs12594549 rs1864416 0.85 A 0.250 0.0049586.00 UNC13C rs8025195 rs8025195 N/A G 0.208 0.04687 0.34 UNC13Crs9302181 rs8025195 0.78 G 0.208 0.04687 0.34 AKAP13 rs16977252rs16949988 0.56 T 0.583 0.01303 3.23 AKAP13 rs338556 rs2241269 0.54 T0.458 0.0371 2.73 SV2B rs1075840 rs6496780 0.74 G 0.167 0.04248 0.31SV2B rs11630131 rs17516708 0.66 T 0.000 0.02337 0.00 SV2B rs2073967rs17516708 0.55 T 0.000 0.02337 0.00 SV2B rs2301665 rs6496780 0.87 G0.167 0.04248 0.31 NETO2 rs11859615 rs9928466 0.85 C 0.125 0.01646 10.43NETO2 rs16952126 rs9928466 0.85 C 0.125 0.01646 10.43 NETO2 rs7184206rs9928466 1.00 C 0.125 0.01646 10.43 NETO2 rs9923731 rs9928466 0.85 C0.125 0.01646 10.43 CBLN1 rs11076478 rs12598711 0.89 G 0.458 0.0040684.10 CBLN1 rs9935379 rs12598711 0.72 G 0.458 0.004068 4.10 CDH11 rs35144rs4967886 0.65 A 0.625 0.04807 2.56 PMP22 rs179521 rs2323653 0.88 A0.458 0.0371 2.73 FUSSEL18 rs10502880 rs11663646 0.55 T 0.583 0.047652.54 FUSSEL18 rs17785419 rs11663646 0.55 T 0.583 0.04765 2.54 DCCrs4940251 rs4940259 0.51 A 0.500 0.03013 2.80 DCC rs6508235 rs49402591.00 A 0.500 0.03013 2.80

Example 7 Novel Markers Associated with Overall Response

To assess drug response, the last observation for each patient intreatment Phase 1 of the CATIE trial was used as a primary assessment ofefficacy. The standard FDA registration trial definition of response of≧20% decrease in Positive and Negative Syndrome Scale (PANSS TotalScore) was used to assign subjects to a response category. Individualshaving composite ordinal effectiveness outcome (COMPEFF) scores of 1 of2, indicating efficacy, were combined as were those with scores of 3 or4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80(2003)). The side effects category consisted of individuals discontinuedfor safety concerns (COMPEFF score 5).

Genetic analysis to document the influence of haplotypes on overallresponse regardless of the drug used was performed using as described inExample 2 with the PLINK 1.03 whole genome analysis toolset developed byPurcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81:559-575(2007)). PLINK calculates P values for the allele-specific chi-squaredtest and the odds ratio (OR; or relative risk) associated with the minorallele.

Confirmation of SNP Effects on Overall Response and Side Effects for allDrugs:

Tables 12 and 13 report the minor allele frequencies, P values, and ORsfor SNPs, in Tables B and C that affect overall response for all drugscombined and side effect rates for all drugs combined, respectively; fora combined sample set of patients treated with the drugs described inExamples 2 through 6. Note in Tables 12 and 13 that haplotype blocksresult in the same Test SNP being in linkage disequilibrium withmultiple SNPs in Table B Similarly, haplotype blocks result in multipleTest SNPs that can be used for each SNP listed in Table B, though suchredundant examples are not presented in Tables 12 and 13.

Tables 12 and 13, provide numerous examples of SNP-based alleles thatpredict altered response for all drugs combined (see Examples 2 through6). For Table 12, ORs of >1.0 indicate that the minor SNP allele isassociated with greater clinical improvement, and ORs of <1.0 indicatethat the minor SNP allele is associated with lesser clinicalimprovement. For Table 13 ORs of >1.0 indicate that the minor SNP alleleis associated with an increase in study ending side effects, and ORs of<1.0 indicate that the minor SNP allele is associated a decrease instudy ending side effects.

TABLE 12 Alleles Affecting Positive Response to For All Drugs CombinedTest SNP Frequency Gene Table in linkage in Name B SNP disequilibrium r²Allele responders P OR PRDM2 rs1203682 rs1203682 N/A C 0.159 0.040250.67 SLC6A17 rs1010892 rs6689641 0.87 A 0.387 0.02751 0.72 SLC6A17rs6689641 rs6689641 N/A A 0.387 0.02751 0.72 SLC6A17 rs877068 rs66896410.75 A 0.387 0.02751 0.72 KCND3 rs11102342 rs1538388 0.90 A 0.451 0.01181.45 DNM3 rs10752946 rs9425598 1.00 A 0.468 0.02928 1.38 DNM3 rs4382763rs6701929 0.84 C 0.199 0.01233 0.64 KCNH1 rs1770220 rs1777256 1.00 A0.331 0.03394 0.72 EXOC2 rs2493037 rs2473484 1.00 C 0.171 0.02535 1.58USH1C rs1055574 rs4756895 0.52 T 0.518 0.02037 1.40 USH1C rs1055577rs4756895 0.52 T 0.518 0.02037 1.40 USH1C rs16770 rs2237961 0.92 C 0.0670.01527 0.52 USH1C rs2072225 rs4756895 0.64 T 0.518 0.02037 1.40 USH1Crs4756895 rs4756895 N/A T 0.518 0.02037 1.40 LRRC4C rs2953310 rs2953310N/A C 0.338 0.02054 0.70 HSD17B12 rs1061810 rs10838184 0.65 C 0.2220.04552 0.71 HSD17B12 rs10838160 rs7482725 0.62 A 0.514 0.03771 1.36HSD17B12 rs3802891 rs7482725 0.62 A 0.514 0.03771 1.36 HSD17B12rs4755744 rs10838184 0.72 C 0.222 0.04552 0.71 KIAA1853 rs6490226rs7966721 0.53 G 0.436 0.01646 1.43 KIAA1545 rs7294615 rs4242909 0.60 C0.407 0.03532 0.73 JPH4 rs12897422 rs12897422 N/A A 0.159 0.02094 1.64DAAM1 rs1252989 rs8004164 0.91 A 0.372 0.02642 0.72 DAAM1 rs1253005rs8004164 0.97 A 0.372 0.02642 0.72 DAAM1 rs4901909 rs8004164 0.60 A0.372 0.02642 0.72 DAAM1 rs8022614 rs8004164 0.74 A 0.372 0.02642 0.72DAAM1 rs941884 rs8004164 0.69 A 0.372 0.02642 0.72 GPR135 rs10136708rs4898989 0.61 A 0.450 0.02522 1.40 GPR135 rs10138199 rs4898989 1.00 A0.450 0.02522 1.40 GPR135 rs1253181 rs4898989 0.81 A 0.450 0.02522 1.40GPR135 rs17255731 rs4898989 0.51 A 0.450 0.02522 1.40 GPR135 rs4898989rs4898989 N/A A 0.450 0.02522 1.40 GPR135 rs9323348 rs4898989 1.00 A0.450 0.02522 1.40 RTN1 rs10145080 rs17731838 0.65 T 0.187 0.02742 0.67RTN1 rs12717467 rs17731838 0.52 T 0.187 0.02742 0.67 RTN1 rs17310036rs17731838 0.81 T 0.187 0.02742 0.67 EML1 rs10144785 rs17099031 0.63 C0.197 0.0419 1.48 UNC13C rs12910912 rs12910912 N/A G 0.229 0.004504 1.68NEDD4 rs2271289 rs12916104 0.86 T 0.458 0.03201 1.37 NEDD4 rs2303579rs10518831 0.51 G 0.183 0.01556 1.62 NEDD4 rs2303580 rs10518831 0.51 G0.183 0.01556 1.62 GRINL1A rs4774275 rs1873995 0.51 G 0.416 0.02634 0.72GRINL1A rs986868 rs9302201 0.90 C 0.405 0.003219 1.56 AKAP13 rs11073502rs2291048 0.53 A 0.232 0.02934 0.69 AKAP13 rs745191 rs745191 N/A T 0.2480.04875 0.72 SV2B rs1075840 rs2106692 0.52 A 0.324 0.03372 1.40 SV2Brs1117388 rs2106692 0.61 A 0.324 0.03372 1.40 SV2B rs11630131 rs64967780.55 G 0.309 0.002113 1.66 SV2B rs2073967 rs6496778 0.87 G 0.3090.002113 1.66 SV2B rs2301665 rs2106692 0.56 A 0.324 0.03372 1.40 SV2Brs11630131 rs11630131 N/A A 0.211 0.03028 1.50 RGMA rs13167 rs110741300.59 T 0.121 0.02593 1.72 IGF1R rs2684808 rs951715 0.51 G 0.303 0.01540.69 CDH11 rs35144 rs4967886 0.65 A 0.335 0.001908 0.62 CDH11 rs35148rs35140 0.68 G 0.264 0.002194 0.61 CDH11 rs35186 rs35140 0.56 G 0.2640.002194 0.61 CDH11 rs35195 rs35195 N/A A 0.271 0.003523 0.63 CDH11rs35144 rs35144 N/A C 0.279 0.006589 0.65 CDH11 rs35186 rs35186 N/A T0.419 0.02642 0.72 FUSSEL18 rs892583 rs11877471 0.68 G 0.377 0.011381.48 FUSSEL18 rs892583 rs892583 N/A G 0.323 0.02405 1.44 SMAD2rs12457664 rs10502890 1.00 T 0.433 0.04215 0.74 SMAD2 rs1787176rs10502890 0.82 T 0.433 0.04215 0.74 SMAD2 rs1792666 rs10502890 0.62 T0.433 0.04215 0.74 SMAD2 rs1792682 rs10502890 0.79 T 0.433 0.04215 0.74SMAD2 rs2000709 rs10502890 0.94 T 0.433 0.04215 0.74 SMAD2 rs7228393rs10502890 0.94 T 0.433 0.04215 0.74 SMAD7 rs736839 rs2337153 0.73 A0.433 0.003271 1.55 SMAD4 rs12458752 rs7243135 0.97 G 0.451 0.04012 1.35SMAD4 rs12958604 rs7243135 0.97 G 0.451 0.04012 1.35 SMAD4 rs2276163rs7243135 0.97 G 0.451 0.04012 1.35 SMAD4 rs2298617 rs7243135 0.97 G0.451 0.04012 1.35 SMAD4 rs3764465 rs7243135 0.97 G 0.451 0.04012 1.35SMAD4 rs620898 rs7243135 0.97 G 0.451 0.04012 1.35 DCC rs12457407rs9949949 0.83 A 0.426 0.00489 1.53 DCC rs1393331 rs8088048 0.78 C 0.4360.02862 1.39 DCC rs1431748 rs7504750 0.63 C 0.329 0.005512 1.57 DCCrs2229080 rs12605899 0.53 C 0.422 0.03279 0.73 DCC rs4940251 rs99499490.82 A 0.426 0.00489 1.53 DCC rs6508235 rs9954344 0.62 G 0.418 0.013421.45 DCC rs7506904 rs9949949 0.93 A 0.426 0.00489 1.53 DCC rs950278rs12605899 0.97 C 0.422 0.03279 0.73

TABLE 13 Alleles Increasing Negative Side Effects for All Drugs CombinedTest SNP Frequency Gene Table in linkage in Name B SNP disequilibrium r²Allele discontinuers P OR CAMTA1 rs228651 rs11121029 0.51 A 0.154 0.03690.61 RERE rs6698830 rs12024032 0.90 C 0.364 0.01972 0.66 RERE rs7530745rs12024032 0.55 C 0.364 0.01972 0.66 RERE rs7554486 rs12024032 0.80 C0.364 0.01972 0.66 KCNA10 rs1281174 rs1281177 0.60 A 0.413 0.04816 1.43KCNA10 rs1281177 rs1281177 N/A A 0.413 0.04816 1.43 CACNA1E rs506947rs593413 1.00 A 0.082 0.0313 0.52 SYT14 rs4609425 rs12029138 0.96 G0.414 0.03589 1.46 EXOC2 rs2493049 rs12154040 0.54 C 0.488 0.03739 1.44NAV2 rs2028570 rs1867116 0.90 T 0.500 0.02091 1.50 NAV2 rs7125647rs2119981 0.61 A 0.380 0.04636 0.70 SLC17A6 rs11026523 rs2078352 0.79 T0.138 0.01 0.53 SLC17A6 rs1155821 rs2078352 0.96 T 0.138 0.01 0.53SLC17A6 rs2078352 rs2078352 N/A T 0.138 0.01 0.53 SLC17A6 rs2246710rs2078352 1.00 T 0.138 0.01 0.53 DAAM1 rs1252989 rs8004164 0.91 A 0.5130.01324 1.55 DAAM1 rs1253005 rs8004164 0.97 A 0.513 0.01324 1.55 DAAM1rs1268579 rs2053298 1.00 T 0.253 0.02417 0.64 DAAM1 rs4127823 rs125893510.61 C 0.338 0.02459 0.66 DAAM1 rs4901909 rs8004164 0.60 A 0.513 0.013241.55 DAAM1 rs8022614 rs8004164 0.74 A 0.513 0.01324 1.55 DAAM1 rs941884rs8004164 0.69 A 0.513 0.01324 1.55 GPR135 rs10136708 rs1253170 0.67 T0.319 0.01197 0.63 GPR135 rs10138199 rs1253170 0.54 T 0.319 0.01197 0.63GPR135 rs1253181 rs1253170 0.74 T 0.319 0.01197 0.63 GPR135 rs4898989rs1253170 0.54 T 0.319 0.01197 0.63 GPR135 rs9323348 rs1253170 0.54 T0.319 0.01197 0.63 EVL rs1190956 rs10136836 0.71 T 0.049 0.02337 0.43WDR25 rs10873518 rs8005782 1.00 A 0.468 0.007603 1.61 HERC2 rs1635168rs6497292 0.87 G 0.130 0.01823 1.91 HERC2 rs2238289 rs6497292 0.51 G0.130 0.01823 1.91 HERC2 rs7495174 rs6497292 0.58 G 0.130 0.01823 1.91UNC13C rs11856476 rs8024165 0.84 T 0.352 0.01767 1.55 UNC13C rs12914912rs8024165 0.63 T 0.352 0.01767 1.55 UNC13C rs4776216 rs8024165 0.52 T0.352 0.01767 1.55 ADAM10 rs3764196 rs7164844 0.51 C 0.074 0.00561 0.42ADAM10 rs4775086 rs605928 0.59 G 0.222 0.03434 0.65 ADAM10 rs514049rs605928 0.73 G 0.222 0.03434 0.65 ADAM10 rs653765 rs605928 0.89 G 0.2220.03434 0.65 CDH11 rs1520233 rs1520233 N/A A 0.309 0.03062 0.67 CDH11rs35144 rs40115 1.00 T 0.438 0.001518 1.77 CDH11 rs35148 rs40115 0.68 T0.438 0.001518 1.77 CDH11 rs35186 rs40115 0.56 T 0.438 0.001518 1.77CDH11 rs35195 rs35195 N/A A 0.438 0.002584 1.71 CDH11 rs35144 rs35144N/A C 0.430 0.009028 1.60 CDH11 rs35186 rs35186 N/A T 0.544 0.04441 1.43BEAN rs4247350 rs1063438 0.59 A 0.265 0.01355 0.62 KIAA0182 rs3815794rs7195186 0.75 G 0.488 0.009922 1.57 KIAA0182 rs736845 rs736845 N/A T0.231 0.01238 0.60 C16orf74 rs2305357 rs394623 0.55 C 0.321 0.04089 0.69C16orf74 rs373835 rs394623 0.68 C 0.321 0.04089 0.69 C16orf74 rs386061rs394623 0.68 C 0.321 0.04089 0.69

Example 8 Novel Markers Associated with Overall PsychiatricEndophenotypes in SZ

Genotype and PANNS phonotype data were evaluated for 417 SZ patientsenrolled in the CATIE trial. Following a period of drug wash-out, theCATIE study investigators rated each participant at baseline forpsychopathology using the PANSS.

Each of the individual and composite scores is a quantitative trait thatcan be assessed using quantitative statistical genetics methods. Geneticanalysis to determine the influence of haplotypes on quantitative PANSSvalues was performed using the PLINK 1.03 whole genome analysis toolsetdeveloped by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet.81:559-575 (2007)).

Confirmation of SNP Effects on Psychiatric Endophenotypes:

Tables 14 and 15 show numerous examples of novel alleles that affect thevalues obtained for specific psychiatric endophenotypes. Note in Tables14 and 15 that haplotype blocks result in the same Test SNP being inlinkage disequilibrium with multiple SNPs in Table B Similarly,haplotype blocks result in multiple Test SNPs that can be used for eachSNP listed in Table B, though such redundant examples are not presentedin Tables 12 and 13 unless different test SNPs influence differentpsychiatric endophenotypes.

Tables 14 and 15 report results for specific SNP alleles that affectquantitative endophenotypes for SZ, along with Beta values and P valuesfor the particular alleles of SNPs listed in Tables B and C. The Beta,beta weight from the regression, measures the impact of the SNP alleleon the particular scale. A positive Beta means that the allele for thetest SNP increases the score for that measure of psychopathology by theBeta value, while a negative Beta means that the allele for the test SNPdecreases the score that for that measure of psychopathology by the Betavalue.

Table 14 shows selected examples for PANSS Total score, PositiveSymptoms subscale, Negative Symptoms subscale, and the GeneralPsychopathology subscale, analyzed as quantitative traits in PLINK usinglinear regression.

Table 15 shows selected examples for the individual PANSS components.The component evaluated in each row is identified by one of thefollowing abbreviations: Positive Symptoms: P1-delusions, P2-conceptualdisorganization, P3-hallucinatory behavior, P4-exitement,P5-grandiosity, P6-suspiciousness, P7-hostility; Negative Symptoms:N1-blunted affect, N2-emotional withdrawal, N3-poor rapport,N4-passive/appathetic social withdrawal, N5-difficulty in abstractthinking, N6-lack of spontaneity and flow of conversation,N7-stereotyped thinking; General Psychopathology Symptoms: G1-somaticconcern, G2-anxiety, G3-guilt feelings, G4-tension, G5-mannerisms andposturing, G6-depression, G7-motor retardation, G8-uncooperativeness,G9-unusual thought content, G10-disorientation, G11-poor attention,G12-lack of judgment and insight, G13 disturbance of volition, G14-poorimpulse control, G15-preoccupation, G16-active social avoidance.

TABLE 14 Alleles Influencing Composite Psychiatric Endophenotypes TestSNP Gene Table in linkage Name B SNP disequilibrium r² Allele PANSS BetaP CAMTA1 rs12070592 rs9434833 1.00 T Positive −1.25 0.02983 CAMTA1rs12070592 rs2071918 1.00 T General −1.83 0.0474 CAMTA1 rs1011124rs1616122 0.63 C General −1.60 0.01229 CAMTA1 rs1417986 rs2301488 0.54 TNegative 1.05 0.02118 PER3 rs707463 rs228688 0.75 T Negative −1.020.0273 PER3 rs707465 rs228688 0.81 T Negative −1.02 0.0273 RP1-21O18.1rs938249 rs4661563 0.66 G Negative −0.90 0.0453 DNM3 rs4382763rs12410416 1.00 C Positive 0.97 0.04342 DNM3 rs4382763 rs7550558 0.84 GTotal 3.38 0.01491 DNM3 rs4382763 rs2586389 0.84 A Negative 1.24 0.01611FASLG rs10458360 rs10458360 N/A C General −1.85 0.005609 FASLGrs12135884 rs10458360 0.56 C General −1.85 0.005609 FASLG rs10458360rs10458360 N/A C Total −2.67 0.03637 FASLG rs12135884 rs10458360 0.56 CTotal −2.67 0.03637 CACNA1E rs17494681 rs17494681 N/A T Negative −1.600.006522 CACNA1E rs199960 rs1953690 0.81 A General 1.39 0.04994 CACNA1Ers3856090 rs7534913 0.50 A General 1.31 0.04178 CACNA1E rs4652678rs17693196 0.50 T General 2.21 0.01456 CACNA1E rs704326 rs704331 0.64 GNegative −1.27 0.005535 CAMK1G rs2356933 rs6683256 1.00 T General −1.450.03081 CAMK1G rs2356933 rs6683256 1.00 T Total −3.00 0.019 CAMK1Grs17014820 rs10489339 0.70 G Total 3.79 0.0419 KCNH1 rs1770213 rs75464720.89 C General 1.91 0.01334 KCNH1 rs1770213 rs7546472 0.89 C Positive1.31 0.006236 KCNH1 rs1770213 rs7546472 0.89 C Total 3.93 0.007621 KCNH1rs4620600 rs4951495 0.79 A Negative 1.37 0.01718 KCNH1 rs4620600rs11119679 0.83 A Positive −1.16 0.0231 EXOC2 rs2493037 rs2473484 1.00 CPositive −1.24 0.03906 ANK3 rs10733757 rs10761446 0.90 C Negative −1.130.03077 ANK3 rs4568956 rs10761446 0.57 C Negative −1.13 0.03077 ANK3rs7907721 rs10761446 0.50 C Negative −1.13 0.03077 RHOG rs1055640rs1055640 N/A G Positive −0.87 0.03465 RHOG rs11030008 rs11030008 N/A GGeneral 1.44 0.02802 RHOG rs1451722 rs11030008 0.76 G General 1.440.02802 RHOG rs11030008 rs11030008 N/A G Positive 1.35 0.000922 RHOGrs1451722 rs11030008 0.76 G Positive 1.35 0.000922 RHOG rs11030008rs11030008 N/A G Total 3.22 0.01005 RHOG rs1451722 rs11030008 0.76 GTotal 3.22 0.01005 USH1C rs1064074 rs1064074 N/A C Negative 0.88 0.04895USH1C rs2072225 rs1064074 0.54 C Negative 0.88 0.04895 USH1C rs16770rs2237961 0.92 C Positive 1.61 0.014 OTOG rs10832824 rs7111528 0.75 TTotal −2.73 0.04189 OTOG rs2023483 rs7111528 0.70 T Total −2.73 0.04189OTOG rs2041028 rs7111528 1.00 T Total −2.73 0.04189 OTOG rs7111528rs7111528 N/A T Total −2.73 0.04189 OTOG rs1003490 rs11024348 0.77 TGeneral −1.65 0.03189 OTOG rs10832824 rs11024348 0.52 T General −1.650.03189 OTOG rs2023483 rs11024348 0.50 T General −1.65 0.03189 SERGEFrs4757589 rs11024415 0.63 C General 1.28 0.04742 PTPN5 rs1550870rs7950091 0.84 T General −1.57 0.01419 PTPN5 rs6483524 rs7950091 0.50 TGeneral −1.57 0.01419 PTPN5 rs10766500 rs11024782 0.93 T General −1.820.009458 PTPN5 rs10766500 rs11024782 0.93 T Negative −0.98 0.04673 PTPN5rs10766500 rs11024782 0.93 T Total −2.97 0.0268 NAV2 rs10833202rs11025328 0.61 G General −1.66 0.01012 NAV2 rs6483629 rs12099330 0.59 TPositive −1.61 0.01255 SLC6A5 rs1443547 rs16906507 0.54 A General 1.510.0386 SLC6A5 rs894750 rs16906507 0.77 A General 1.51 0.0386 SLC6A5rs1443547 rs16906507 0.54 A Total 2.97 0.03352 SLC6A5 rs894750rs16906507 0.77 A Total 2.97 0.03352 LRRC4C rs10837367 rs10501227 1.00 GPositive −1.66 0.04454 SYT13 rs2863172 rs4755941 0.80 A General 2.400.02256 SYT13 rs2863174 rs4755941 0.88 A General 2.40 0.02256 SYT13rs4755941 rs4755941 N/A A General 2.40 0.02256 SYT13 rs7103871 rs47559410.84 A General 2.40 0.02256 KIAA1853 rs6490226 rs1568922 0.91 C General−1.83 0.01852 KIAA1853 rs6490226 rs1568922 0.91 C Positive −1.07 0.02697KIAA1853 rs6490226 rs1568922 0.91 C Total −3.74 0.0115 KIAA1853rs7136574 rs4298970 0.72 A General 1.46 0.03329 KIAA1853 rs7136574rs4075946 0.82 T Positive −0.91 0.02171 KIAA1853 rs7136574 rs40759460.82 T Total −2.54 0.03892 KIAA1853 rs1541764 rs1541764 N/A G General1.52 0.01871 KIAA1853 rs2555269 rs1541764 0.51 G General 1.52 0.01871KIAA1853 rs2723880 rs1541764 0.74 G General 1.52 0.01871 KIAA1853rs2723882 rs1541764 0.55 G General 1.52 0.01871 KIAA1853 rs1541764rs1541764 N/A G Negative 1.18 0.009674 KIAA1853 rs2555269 rs1541764 0.51G Negative 1.18 0.009674 KIAA1853 rs2723880 rs1541764 0.74 G Negative1.18 0.009674 KIAA1853 rs2723882 rs1541764 0.55 G Negative 1.18 0.009674KIAA1853 rs1541764 rs1541764 N/A G Total 3.21 0.009581 KIAA1853rs2555269 rs1541764 0.51 G Total 3.21 0.009581 KIAA1853 rs2723880rs1541764 0.74 G Total 3.21 0.009581 KIAA1853 rs2723882 rs1541764 0.55 GTotal 3.21 0.009581 STX2 rs1236 rs7956851 0.81 C Negative −0.99 0.04055STX2 rs4759517 rs7956851 1.00 C Negative −0.99 0.04055 STX2 rs6486600rs7956851 0.97 C Negative −0.99 0.04055 STX2 rs6486602 rs7956851 1.00 CNegative −0.99 0.04055 TTC5 rs2318864 rs4981148 0.52 T General −1.690.04301 TTC5 rs3737220 rs4981148 0.51 T General −1.69 0.04301 TTC5rs3742945 rs4981148 0.52 T General −1.69 0.04301 TTC5 rs2318864rs4981148 0.52 T Total −3.18 0.04708 TTC5 rs3737220 rs4981148 0.51 TTotal −3.18 0.04708 TTC5 rs3742945 rs4981148 0.52 T Total −3.18 0.04708TEP1 rs1713449 rs1713448 0.96 A General 1.55 0.0488 TEP1 rs7150689rs1713448 0.87 A General 1.55 0.0488 TEP1 rs938886 rs1713448 1.00 AGeneral 1.55 0.0488 TEP1 rs938887 rs1713448 0.67 A General 1.55 0.0488JPH4 rs12897422 rs12897422 N/A A General −2.40 0.0136 JPH4 rs12897422rs12897422 N/A A Negative −2.00 0.003322 JPH4 rs12897422 rs12897422 N/AA Total −5.10 0.00594 DAAM1 rs10143918 rs10483710 0.58 A Negative −1.480.01586 DAAM1 rs12147707 rs10483710 0.86 A Negative −1.48 0.01586 DAAM1rs17095965 rs10483710 0.86 A Negative −1.48 0.01586 DAAM1 rs1252989rs4901909 0.62 T Positive 0.83 0.04088 DAAM1 rs1253005 rs4901909 0.62 TPositive 0.83 0.04088 DAAM1 rs4901909 rs4901909 N/A T Positive 0.830.04088 DAAM1 rs8022614 rs4901909 0.60 T Positive 0.83 0.04088 DAAM1rs941884 rs4901909 0.85 T Positive 0.83 0.04088 DAAM1 rs10143918rs6573250 0.69 T General −1.52 0.01672 DAAM1 rs11626926 rs1547199 0.85 TGeneral 1.37 0.03582 DAAM1 rs4127823 rs1271513 0.65 C General −1.570.02025 DAAM1 rs941886 rs1271513 1.00 C General −1.57 0.02025 EML1rs2250718 rs3783322 0.70 G General 1.54 0.01544 EML1 rs2250718 rs37833220.70 G Negative 1.10 0.01418 EML1 rs2250718 rs3783322 0.70 G Total 2.620.03153 EML1 rs11160553 rs11160554 1.00 C Negative −1.83 0.000141 EML1rs11160563 rs11160554 0.56 C Negative −1.83 0.000141 EML1 rs12433613rs11160554 0.88 C Negative −1.83 0.000141 EML1 rs6575751 rs11160554 1.00C Negative −1.83 0.000141 EML1 rs746698 rs10131519 0.91 C Positive 1.070.03808 EML1 rs746698 rs10131519 0.91 C Total 3.17 0.04577 EML1rs2273707 rs2250718 0.53 T General 1.29 0.04771 EML1 rs2273704 rs38182790.58 G Negative 1.53 0.004398 EML1 rs746698 rs3818279 0.71 G Negative1.53 0.004398 EML1 rs11160553 rs4900447 0.59 A General −2.06 0.002015EML1 rs11160563 rs4900447 0.97 A General −2.06 0.002015 EML1 rs12433613rs4900447 0.51 A General −2.06 0.002015 EML1 rs6575751 rs4900447 0.59 AGeneral −2.06 0.002015 EML1 rs11160553 rs4900447 0.59 A Total −4.440.000493 EML1 rs11160563 rs4900447 0.97 A Total −4.44 0.000493 EML1rs12433613 rs4900447 0.51 A Total −4.44 0.000493 EML1 rs6575751rs4900447 0.59 A Total −4.44 0.000493 HERC2 rs11631797 rs916977 0.86 TNegative 1.26 0.01939 HERC2 rs2238289 rs916977 0.79 T Negative 1.260.01939 HERC2 rs916977 rs916977 N/A T Negative 1.26 0.01939 UNC13Crs17731958 rs17731958 N/A T General −3.74 0.01791 UNC13C rs2163195rs8024845 1.00 G Negative 0.97 0.04595 UNC13C rs489526 rs573320 0.70 ANegative −1.04 0.04416 UNC13C rs489526 rs500853 1.00 G Total −2.760.03901 UNC13C rs16974691 rs16974712 0.96 T General −1.57 0.04754 UNC13Crs16974691 rs16974712 0.96 T Negative −1.39 0.01224 UNC13C rs16974691rs16974712 0.96 T Total −3.83 0.01099 Gcom1 rs4774275 rs9806498 1.00 TPositive 0.98 0.01975 GCOM1 rs16977629 rs16977629 N/A T Negative 2.210.01041 Gcom1 rs16977631 rs16977629 0.56 T Negative 2.21 0.01041 GRINL1Ars986868 rs7176042 0.75 A Positive −0.99 0.01843 AKAP13 rs745191rs745191 N/A T Positive 0.99 0.02393 AKAP13 rs11073502 rs2291048 0.53 APositive 1.22 0.006071 AKAP13 rs2241268 rs2241268 N/A A Positive 1.040.01761 KLHL25 rs11637212 rs11637212 N/A G Positive 1.07 0.01597 SV2Brs11630131 rs11631712 0.55 C Negative −1.50 0.002999 SV2B rs2073967rs11631712 0.87 C Negative −1.50 0.002999 SLCO3A1 rs2286355 rs116308720.85 T Negative −0.99 0.04033 IGF1R rs7170035 rs4966012 0.55 C Negative−1.04 0.03039 IGF1R rs4965436 rs11634874 0.76 C Positive 1.43 0.02266IGF1R rs2684792 rs7173377 0.96 C Positive 1.22 0.0019 CBLN1 rs11076478rs1469906 0.72 A Negative −1.15 0.01235 CBLN1 rs9935379 rs1469906 0.90 ANegative −1.15 0.01235 ZNF423 rs12924119 rs4785185 0.50 T Positive −1.040.03187 CDH8 rs4131634 rs11862752 0.51 A General −2.74 0.006021 CDH8rs4131634 rs11862752 0.51 A Total −4.07 0.03321 CDH8 rs9939991rs13336134 0.55 C Positive −0.99 0.01792 CDH8 rs11075445 rs7189354 1.00G Positive −1.23 0.002488 CDH8 rs1369918 rs7189354 1.00 G Positive −1.230.002488 CDH8 rs1978796 rs7189354 1.00 G Positive −1.23 0.002488 CDH8rs6498807 rs7189354 0.80 G Positive −1.23 0.002488 CDH8 rs1397131rs16964164 0.90 T Negative 0.91 0.04219 CDH8 rs8057338 rs16964164 0.93 TNegative 0.91 0.04219 CDH8 rs9302540 rs16964164 0.93 T Negative 0.910.04219 CDH11 rs1520233 rs4625747 0.67 T General −1.51 0.02769 CDH11rs35148 rs35162 1.00 A General 1.73 0.01682 CDH11 rs35144 rs35162 0.68 APositive 1.14 0.01107 CDH11 rs35148 rs35162 1.00 A Positive 1.14 0.01107CDH11 rs35144 rs35162 0.68 A Total 3.04 0.02738 CDH11 rs35148 rs351621.00 A Total 3.04 0.02738 CDH11 rs35186 rs35140 0.56 G Positive 0.910.0272 CDH11 rs35195 rs35195 N/A A General 1.45 0.02761 CDH11 rs35195rs35195 N/A A Positive 0.87 0.03339 CDH11 rs35144 rs35186 0.56 T General1.58 0.0137 CDH11 rs35186 rs35186 N/A T General 1.58 0.0137 CDH11rs35186 rs35186 N/A T Total 2.57 0.03558 KIAA0182 rs1049868 rs7324600.58 T Negative 1.11 0.03822 KIAA0182 rs3815795 rs732460 0.59 T Negative1.11 0.03822 PMP22 rs13422 rs192046 0.93 T General 1.28 0.03702 PMP22rs230938 rs192046 0.67 T General 1.28 0.03702 PMP22 rs179521 rs116564870.83 C General −1.41 0.02417 PMP22 rs231018 rs11656487 0.52 C General−1.41 0.02417 PMP22 rs179521 rs11656487 0.83 C Total −2.48 0.03766 PMP22rs231018 rs11656487 0.52 C Total −2.48 0.03766 KATNAL2 rs2187092rs2010834 0.97 A General 2.27 0.0008 KATNAL2 rs2247221 rs2010834 0.56 AGeneral 2.27 0.0008 KATNAL2 rs2571030 rs2010834 0.56 A General 2.270.0008 KATNAL2 rs2576042 rs2010834 0.59 A General 2.27 0.0008 KATNAL2rs7233515 rs2010834 0.69 A General 2.27 0.0008 KATNAL2 rs9304340rs2010834 0.97 A General 2.27 0.0008 KATNAL2 rs2187092 rs2010834 0.97 ANegative 1.18 0.01344 KATNAL2 rs2247221 rs2010834 0.56 A Negative 1.180.01344 KATNAL2 rs2571030 rs2010834 0.56 A Negative 1.18 0.01344 KATNAL2rs2576042 rs2010834 0.59 A Negative 1.18 0.01344 KATNAL2 rs7233515rs2010834 0.69 A Negative 1.18 0.01344 KATNAL2 rs9304340 rs2010834 0.97A Negative 1.18 0.01344 KATNAL2 rs2187092 rs2010834 0.97 A Total 4.450.000588 KATNAL2 rs2247221 rs2010834 0.56 A Total 4.45 0.000588 KATNAL2rs2571030 rs2010834 0.56 A Total 4.45 0.000588 KATNAL2 rs2576042rs2010834 0.59 A Total 4.45 0.000588 KATNAL2 rs7233515 rs2010834 0.69 ATotal 4.45 0.000588 KATNAL2 rs9304340 rs2010834 0.97 A Total 4.450.000588 KATNAL2 rs9961383 rs2571034 0.60 G General 1.61 0.01919 KATNAL2rs9961383 rs2571034 0.60 G Total 2.68 0.04215 KATNAL2 rs2187092rs2576040 0.57 T Positive −1.02 0.01334 KATNAL2 rs2247221 rs2576040 0.61T Positive −1.02 0.01334 KATNAL2 rs2571030 rs2576040 0.61 T Positive−1.02 0.01334 KATNAL2 rs2576042 rs2576040 1.00 T Positive −1.02 0.01334KATNAL2 rs7233515 rs2576040 0.51 T Positive −1.02 0.01334 KATNAL2rs9304340 rs2576040 0.57 T Positive −1.02 0.01334 FUSSEL18 rs10502880rs9304344 0.85 T General −1.48 0.02048 FUSSEL18 rs17785419 rs93043440.85 T General −1.48 0.02048 FUSSEL18 rs2668771 rs9304344 0.64 T General−1.48 0.02048 FUSSEL18 rs7236105 rs9304344 1.00 T General −1.48 0.02048FUSSEL18 rs10502880 rs9304344 0.85 T Positive −0.87 0.02914 FUSSEL18rs17785419 rs9304344 0.85 T Positive −0.87 0.02914 FUSSEL18 rs2668771rs9304344 0.64 T Positive −0.87 0.02914 FUSSEL18 rs7236105 rs93043441.00 T Positive −0.87 0.02914 FUSSEL18 rs10502880 rs9304344 0.85 T Total−2.69 0.02795 FUSSEL18 rs17785419 rs9304344 0.85 T Total −2.69 0.02795FUSSEL18 rs2668771 rs9304344 0.64 T Total −2.69 0.02795 FUSSEL18rs7236105 rs9304344 1.00 T Total −2.69 0.02795 DCC rs6508145 rs10310620.67 G Negative −1.36 0.02919 DCC rs6508145 rs1031062 0.67 G Total −3.340.04901 DCC rs1893572 rs7228674 0.77 T Negative 1.68 0.000333 DCCrs1893572 rs9807201 0.65 A General 1.73 0.01191 DCC rs1893572 rs98072010.65 A Total 3.16 0.01642 DCC rs1431748 rs4998815 0.61 G General −1.470.02576 DCC rs1431748 rs9953016 0.81 C Negative −1.13 0.0172 DCCrs1431748 rs7504750 0.63 C Total −2.97 0.02854 TMEPAI rs427278 rs2033860.51 C General 1.51 0.02214 TMEPAI rs427278 rs203386 0.51 C Total 2.780.02738

TABLE 15 Alleles Influencing Specific Psychiatric Endophenotypes TestSNP Gene Table in linkage Name B SNP disequilibrium r² Allele PANSS BetaP CAMTA1 rs7554752 rs4908575 0.96 C G10 0.18 0.002944 CAMTA1 rs12070592rs2071918 1.00 T G6 −0.42 0.002692 CAMTA1 rs12070592 rs2071918 1.00 T G9−0.38 0.003607 CAMTA1 rs707455 rs697686 0.66 T N7 −0.27 0.002057 PER3rs707463 rs707463 N/A T N7 −0.25 0.004339 PER3 rs707465 rs697686 0.93 TN7 −0.27 0.002057 PER3 rs707463 rs697686 1.00 T N7 −0.27 0.002057 PER3rs2640909 rs228652 0.70 A N5 −0.34 0.002229 RP1-21O18.1 rs12057431rs10803343 1.00 C G14 0.95 0.0002941 RP1-21O18.1 rs4661572 rs10003130.63 G G14 0.28 0.0003008 KCND3 rs3738298 rs584096 0.70 G G10 −0.280.0003434 DNM3 rs4382763 rs2586392 0.84 C N7 0.27 0.003464 CACNA1Ers17494681 rs17494681 N/A T N4 −0.37 0.003546 CACNA1E rs3856090rs10797729 0.70 A G7 0.34 0.0001445 CACNA1E rs199960 rs10797729 0.77 AG7 0.34 0.0001445 CACNA1E rs199960 rs7513540 0.61 T G1 −0.32 0.001712CACNA1E rs4652678 rs17693196 0.50 T G1 0.40 0.002089 CACNA1E rs704326rs704331 0.64 G G7 −0.28 0.0005166 CACNA1E rs704326 rs704331 0.64 G N1−0.32 0.00162 CACNA1E rs704326 rs704331 0.64 G N3 −0.28 0.001365 CACNA1Ers704326 rs704331 0.64 G N6 −0.32 0.0008968 CAMK1G rs17014820 rs75120910.91 A G5 0.29 0.001812 CAMK1G rs6690557 rs713075 0.80 A G5 −0.230.003493 CAMK1G rs17014820 rs7516885 1.00 T N7 0.38 0.0007187 CAMK1Grs17014820 rs10489339 0.70 G G4 0.43 0.0006328 KCNH1 rs1770213 rs75464720.89 C P1 0.39 0.003181 DPH3 rs2245721 rs842264 0.57 T P5 0.30 0.0005309DPH3 rs842257 rs842264 0.57 T P5 0.30 0.0005309 DPH3 rs859703 rs8422640.57 T P5 0.30 0.0005309 DPH3 rs2245708 rs842261 0.67 A P5 0.27 0.004185DPH3 rs2245721 rs842251 1.00 G G10 0.20 0.000734 DPH3 rs842257 rs8422511.00 G G10 0.20 0.000734 DPH3 rs859703 rs842251 1.00 G G10 0.20 0.000734DPH3 rs2245721 rs842259 1.00 T G7 −0.23 0.004115 DPH3 rs842257 rs8422591.00 T G7 −0.23 0.004115 DPH3 rs859703 rs842259 1.00 T G7 −0.23 0.004115EXOC2 rs1473909 rs9405242 0.97 A N5 −0.35 0.0008412 TOLLIP rs3168046rs2014486 0.85 A G7 −0.24 0.001849 TOLLIP rs3750920 rs2014486 0.85 A G7−0.24 0.001849 BRSK2 rs1554857 rs1554857 N/A A G5 −0.23 0.002684 BRSK2rs1554857 rs1108991 0.81 G G5 −0.25 0.001173 HCCA2 rs7945160 rs11089910.55 G G5 −0.25 0.001173 HCCA2 rs9440 rs1108991 0.55 G G5 −0.25 0.001173HCCA2 rs7396514 rs1108991 1.00 G G5 −0.25 0.001173 DUSP8 rs10734456rs1108991 0.55 G G5 −0.25 0.001173 DUSP8 rs902224 rs1108991 0.81 G G5−0.25 0.001173 RHOG rs1055640 rs1055640 N/A G G4 −0.25 0.003073 RHOGrs1451722 rs11030008 0.76 G P1 0.32 0.00439 RHOG rs11030008 rs11030008N/A G P1 0.32 0.00439 RHOG rs1451722 rs11030008 0.76 G P6 0.33 0.001515RHOG rs11030008 rs11030008 N/A G P6 0.33 0.001515 USH1C rs2072225rs1064074 0.54 C G16 0.28 0.002619 USH1C rs1064074 rs1064074 N/A C G160.28 0.002619 USH1C rs16770 rs2237961 0.92 C P4 0.42 0.0007385 OTOGrs2041028 rs757982 0.64 A G12 −0.32 0.0007194 OTOG rs7111528 rs7579820.64 A G12 −0.32 0.0007194 OTOG rs2023483 rs7111528 0.70 T P2 −0.270.008232 OTOG rs10832824 rs7111528 0.75 T P2 −0.27 0.008232 OTOGrs2041028 rs7111528 1.00 T P2 −0.27 0.008232 OTOG rs7111528 rs7111528N/A T P2 −0.27 0.008232 OTOG rs2023483 rs4757560 0.52 C P5 −0.250.008921 PTPN5 rs10766500 rs11024782 0.93 T G16 −0.31 0.002084 PTPN5rs10766500 rs755796 0.93 G G10 −0.19 0.004029 NAV2 rs10833202 rs110253280.61 G G15 −0.25 0.003892 NAV2 rs7125647 rs10833228 0.65 C G11 0.300.0007124 LRRC4C rs2953310 rs2953310 N/A C P4 −0.21 0.004729 LRRC4Crs10837367 rs10501227 1.00 G P1 −0.67 0.003309 HSD17B12 rs1061810rs10838186 0.87 C G5 0.21 0.003535 HSD17B12 rs4755744 rs10838186 1.00 CG5 0.21 0.003535 HSD17B12 rs11037691 rs11037691 N/A A G5 0.39 0.004419SYT13 rs12362429 rs12362444 1.00 G G10 0.21 0.0007107 SYT13 rs12362429rs12362444 1.00 G P2 0.29 0.002839 SYT13 rs4992029 rs1075778 0.61 G P20.27 0.009285 SYT13 rs2863182 rs1075778 0.84 G P2 0.27 0.009285 SYT13rs11038382 rs1075778 1.00 G P2 0.27 0.009285 SYT13 rs4992029 rs64856080.50 C G10 0.20 0.002462 SYT13 rs11038382 rs6485608 0.84 C G10 0.200.002462 SYT13 rs2863182 rs6485608 1.00 C G10 0.20 0.002462 DTX4rs1048444 rs2211912 0.77 A N6 0.32 0.0006063 DTX4 rs3847 rs2211912 0.77A N6 0.32 0.0006063 DTX4 rs656163 rs2211912 0.88 A N6 0.32 0.0006063DTX4 rs5029315 rs2211912 1.00 A N6 0.32 0.0006063 DTX4 rs2211912rs2211912 N/A A N6 0.32 0.0006063 DTX4 rs3847 rs3847 N/A A N6 0.300.003075 DTX4 rs621162 rs544864 1.00 T N6 0.35 0.0008417 DTX4 rs544864rs544864 N/A T N6 0.35 0.0008417 KIAA1853 rs6490226 rs7966721 0.53 G N1−0.32 0.00181 KIAA1853 rs7136574 rs4298970 0.72 A G1 0.28 0.004999RIMBP2 rs4237817 rs1877978 0.55 C G4 0.25 0.003266 TTC5 rs3737220rs4981148 0.51 T G15 −0.32 0.004087 TTC5 rs2318864 rs4981148 0.52 T G15−0.32 0.004087 TTC5 rs3742945 rs4981148 0.52 T G15 −0.32 0.004087 NDRG2rs1243444 rs1243446 0.58 G G15 0.23 0.004573 NDRG2 rs1243446 rs1243446N/A G G15 0.23 0.004573 JPH4 rs12897422 rs12897422 N/A A G2 −0.450.0009928 JPH4 rs12897422 rs12897422 N/A A G6 −0.44 0.002891 JPH4rs12897422 rs12897422 N/A A N4 −0.43 0.003217 DACT1 rs464582 rs464582N/A C G14 −0.19 0.0041 DACT1 rs464582 rs464582 N/A C P4 −0.22 0.004041DACT1 rs464582 rs464582 N/A C P7 −0.21 0.001554 DAAM1 rs12147707rs10483710 0.86 A G13 −0.36 0.0009634 DAAM1 rs17095965 rs10483710 0.86 AG13 −0.36 0.0009634 DAAM1 rs10143918 rs10483710 0.58 A G5 −0.28 0.003772DAAM1 rs12147707 rs10483710 0.86 A G5 −0.28 0.003772 DAAM1 rs17095965rs10483710 0.86 A G5 −0.28 0.003772 DAAM1 rs10143918 rs6573250 0.69 TG13 −0.28 0.0003461 DAAM1 rs941886 rs941886 N/A C G13 −0.24 0.003883DAAM1 rs11626926 rs1547199 0.85 T G13 0.23 0.004418 DAAM1 rs4127823rs1271513 0.65 C G13 −0.25 0.003443 DAAM1 rs941886 rs1271513 1.00 C G13−0.25 0.003443 GPR135 rs17255731 rs4898989 0.51 A P6 −0.29 0.005506GPR135 rs10136708 rs4898989 0.61 A P6 −0.29 0.005506 GPR135 rs1253181rs4898989 0.81 A P6 −0.29 0.005506 GPR135 rs10138199 rs4898989 1.00 A P6−0.29 0.005506 GPR135 rs9323348 rs4898989 1.00 A P6 −0.29 0.005506GPR135 rs4898989 rs4898989 N/A A P6 −0.29 0.005506 GPR135 rs10136708rs1253103 0.54 C G16 −0.27 0.003698 GPR135 rs17255731 rs1253103 0.57 CG16 −0.27 0.003698 GPR135 rs1253181 rs1253103 0.71 C G16 −0.27 0.003698GPR135 rs10138199 rs1253103 0.88 C G16 −0.27 0.003698 GPR135 rs4898989rs1253103 0.88 C G16 −0.27 0.003698 GPR135 rs9323348 rs1253103 0.88 CG16 −0.27 0.003698 RTN1 rs10145080 rs12878097 0.55 C G12 0.32 0.003522RTN1 rs17310036 rs12878097 1.00 C G12 0.32 0.003522 RTN1 rs17310036rs1951366 0.79 A N3 0.26 0.002511 RTN1 rs10145080 rs17256003 0.55 C G80.20 0.0032 RTN1 rs17310036 rs17256003 1.00 C G8 0.20 0.0032 EML1rs2250718 rs3783322 0.70 G G7 0.29 0.0002896 EML1 rs11160563 rs111605540.56 C N1 −0.35 0.001551 EML1 rs11160563 rs11160554 0.56 C N6 −0.300.003367 EML1 rs12433613 rs11160554 0.88 C N6 −0.30 0.003367 EML1rs11160553 rs11160554 1.00 C N6 −0.30 0.003367 EML1 rs6575751 rs111605541.00 C N6 −0.30 0.003367 EML1 rs11160563 rs1957509 0.56 A G7 −0.290.0006263 EML1 rs12433613 rs1957509 0.88 A G7 −0.29 0.0006263 EML1rs11160553 rs1957509 1.00 A G7 −0.29 0.0006263 EML1 rs6575751 rs19575091.00 A G7 −0.29 0.0006263 EML1 rs11160553 rs1191109 0.51 A N1 −0.370.0002563 EML1 rs6575751 rs1191109 0.51 A N1 −0.37 0.0002563 EML1rs11160553 rs1191109 0.51 A N3 −0.28 0.001132 EML1 rs6575751 rs11911090.51 A N3 −0.28 0.001132 EML1 rs12433613 rs1005766 0.77 G N1 −0.350.001409 EML1 rs12433613 rs1005766 0.77 G N4 −0.30 0.003513 EML1rs11160553 rs1005766 0.88 G N4 −0.30 0.003513 EML1 rs6575751 rs10057660.88 G N4 −0.30 0.003513 EML1 rs2273707 rs975252 0.59 T G7 0.26 0.001636EML1 rs2273707 rs2250718 0.53 T G2 0.31 0.0005703 EML1 rs2250718rs2250718 N/A T G2 0.31 0.0005703 EML1 rs2273704 rs3818279 0.58 G N10.41 0.0006622 EML1 rs746698 rs3818279 0.71 G N1 0.41 0.0006622 EML1rs11160563 rs8020741 0.68 T G5 −0.22 0.00144 EML1 rs12433613 rs49004470.51 A G15 −0.31 0.0004618 EML1 rs11160553 rs4900447 0.59 A G15 −0.310.0004618 EML1 rs6575751 rs4900447 0.59 A G15 −0.31 0.0004618 EML1rs11160563 rs4900447 0.97 A G15 −0.31 0.0004618 EML1 rs12433613rs4900447 0.51 A G5 −0.22 0.002755 EML1 rs11160553 rs4900447 0.59 A G5−0.22 0.002755 EML1 rs6575751 rs4900447 0.59 A G5 −0.22 0.002755 EML1rs12433613 rs4900447 0.51 A N7 −0.25 0.003313 EML1 rs11160553 rs49004470.59 A N7 −0.25 0.003313 EML1 rs6575751 rs4900447 0.59 A N7 −0.250.003313 EML1 rs11160563 rs4900447 0.97 A N7 −0.25 0.003313 EVLrs1190956 rs2400848 0.51 C G16 −0.54 0.004824 BEGAIN rs7140556 rs11908620.65 T G14 −0.23 0.001153 HERC2 rs2238289 rs916977 0.79 T N3 0.370.0003766 HERC2 rs11631797 rs916977 0.86 T N3 0.37 0.0003766 HERC2rs916977 rs916977 N/A T N3 0.37 0.0003766 HERC2 rs2238289 rs916977 0.79T N6 0.37 0.001355 HERC2 rs11631797 rs916977 0.86 T N6 0.37 0.001355HERC2 rs916977 rs916977 N/A T N6 0.37 0.001355 UNC13C rs17731958rs17731958 N/A T G6 −0.95 0.00007556 UNC13C rs489526 rs500853 1.00 G N7−0.25 0.004691 UNC13C rs489526 rs500853 1.00 G P2 −0.29 0.004176 UNC13Crs16974691 rs16974712 0.96 T G10 −0.21 0.0047 UNC13C rs16974691rs16974712 0.96 T P2 −0.34 0.003461 Gcom1 rs16977631 rs16977629 0.56 TG16 0.52 0.003424 Gcom1 rs16977629 rs16977629 N/A T G16 0.52 0.003424GRINL1A rs986868 rs1425948 0.97 A P7 −0.21 0.001524 AKAP13 rs745191rs745191 N/A T G9 0.29 0.003429 AKAP13 rs11073502 rs2291048 0.53 A G90.30 0.002606 AKAP13 rs11073502 rs2291048 0.53 A P1 0.37 0.002475 AKAP13rs2241268 rs2241268 N/A A G9 0.28 0.004651 KLHL25 rs11637212 rs11637212N/A G P5 0.26 0.009632 SV2B rs11630131 rs11631712 0.55 C N4 −0.310.003964 SV2B rs2073967 rs11631712 0.87 C N4 −0.31 0.003964 SLCO3A1rs4294800 rs8032981 0.67 A G1 −0.35 0.001287 SLCO3A1 rs4294800 rs9757210.51 G P5 −0.26 0.004699 SLCO3A1 rs2176452 rs975721 0.53 G P5 −0.260.004699 IGF1R rs4965436 rs11634874 0.76 C P5 0.40 0.005139 IGF1Rrs11247380 rs1879613 0.53 A G1 0.39 0.0005785 IGF1R rs1879613 rs1879613N/A A G1 0.39 0.0005785 IGF1R rs2684792 rs7173377 0.96 C G9 0.260.004224 IGF1R rs2684792 rs7173377 0.96 C P3 0.33 0.003003 IGF1Rrs2684792 rs7173377 0.96 C P5 0.27 0.002108 NDRG4 rs42945 rs40359 0.66 CG12 −0.28 0.002966 GOT2 rs2042445 rs7204324 0.51 T P5 −0.41 0.008799CDH8 rs4636897 rs11641508 1.00 A G2 0.44 0.0009623 CDH8 rs4131634rs4416006 0.96 C G5 −0.25 0.002379 CDH8 rs4131634 rs11862752 0.51 A G4−0.39 0.002652 CDH8 rs6498807 rs7189354 0.80 G P1 −0.32 0.004743 CDH8rs11075445 rs7189354 1.00 G P1 −0.32 0.004743 CDH8 rs1369918 rs71893541.00 G P1 −0.32 0.004743 CDH8 rs1978796 rs7189354 1.00 G P1 −0.320.004743 CDH11 rs35144 rs35165 0.68 A G6 0.35 0.001477 CDH11 rs35148rs35165 1.00 A G6 0.35 0.001477 CDH11 rs35144 rs35162 0.68 A G2 0.290.00496 CDH11 rs35148 rs35162 1.00 A G2 0.29 0.00496 KIAA0513 rs4783121rs16975240 0.87 G G6 −0.70 0.002637 PMP22 rs13422 rs231020 0.64 T P3−0.36 0.0008073 PMP22 rs231021 rs231020 0.67 T P3 −0.36 0.0008073 PMP22rs231018 rs231020 0.93 T P3 −0.36 0.0008073 PMP22 rs231018 rs108528300.52 C G13 −0.24 0.001942 PMP22 rs179521 rs10852830 0.83 C G13 −0.240.001942 KATNAL2 rs2247221 rs2010834 0.56 A N7 0.33 0.0001519 KATNAL2rs2571030 rs2010834 0.56 A N7 0.33 0.0001519 KATNAL2 rs2576042 rs20108340.59 A N7 0.33 0.0001519 KATNAL2 rs7233515 rs2010834 0.69 A N7 0.330.0001519 KATNAL2 rs2187092 rs2010834 0.97 A N7 0.33 0.0001519 KATNAL2rs9304340 rs2010834 0.97 A N7 0.33 0.0001519 KIAA0427 rs2175565rs9952398 1.00 C G1 −0.31 0.00361 KIAA0427 rs937021 rs937021 N/A G N50.30 0.003682 DYM rs357894 rs357894 N/A C G9 −0.33 0.0006157 DYMrs498929 rs16950465 0.54 T G9 −0.36 0.001734 DCC rs17753970 rs169547310.87 G G4 0.27 0.004839 DCC rs8089980 rs8089980 N/A T G16 0.27 0.003432DCC rs8089980 rs8089980 N/A T G7 0.24 0.002252 DCC rs8089980 rs108536210.76 T G7 0.25 0.001494 DCC rs8089980 rs10853622 0.76 A G12 −0.270.004596 DCC rs1893572 rs7228674 0.77 T G16 0.28 0.004286 DCC rs1893572rs7228674 0.77 T N1 0.32 0.002084 DCC rs1893572 rs7228674 0.77 T N2 0.260.004955 DCC rs1893572 rs7228674 0.77 T N6 0.28 0.004787 DCC rs1893572rs9807201 0.65 A G7 0.32 0.000156 DCC rs1893572 rs9807201 0.65 A N3 0.300.001024 DCC rs1431748 rs4998815 0.61 G G12 −0.28 0.004202 DCC rs950278rs12967277 0.60 G G12 0.28 0.002738 DCC rs950278 rs12455180 0.53 T P2−0.25 0.008191 DCC rs2229080 rs12455180 0.64 T P2 −0.25 0.008191 DCCrs1431748 rs9953016 0.81 C N2 −0.29 0.001508 DCC rs1431748 rs75047500.63 C G2 −0.32 0.001379 DCC rs8096519 rs11082964 0.95 G N2 0.300.004634 DCC rs12457407 rs9954344 0.61 G P2 −0.27 0.004541 DCC rs6508235rs9954344 0.62 G P2 −0.27 0.004541 DCC rs7506904 rs9954344 0.69 G P2−0.27 0.004541 DCC rs4940251 rs9954344 0.86 G P2 −0.27 0.004541 DCCrs2270954 rs2270954 N/A A P6 −0.46 0.002603 BMP7 rs10375 rs6123669 0.91C G14 −0.21 0.001474 BMP7 rs6014947 rs6123669 0.97 C G14 −0.21 0.001474BMP7 rs230198 rs230198 N/A G G15 −0.25 0.004865

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A method of obtaining information regarding a human subject's risk ofdeveloping schizophrenia (SZ) the method comprising: obtaining a testhaplotype for the subject by determining the genotype of at least onetest marker listed in Table B, or a test marker that lies between a pairof delimiting markers listed in Table A and that is in linkagedisequilibrium with markers listed in Table B, wherein the testhaplotype indicates the subject's risk of developing SZ. 2.-47.(canceled)